Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 18–22, January 2011
Alfredo Alberti
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02378.x
© 2011 John Wiley & Sons A/S
Author Information
Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy
* Correspondence: Correspondence Prof. Alfredo Alberti, Department of Histology, Microbiology and Medical Biotechnologies, Venetian Institute of Molecular Medicine, University of Padova, Via Orus 2, 35100 Padova, Italy Tel: +39 049 821 2293 Fax: +39 049 821 1826 e-mail: alfredo.alberti@gmail.com
Keywords:
cirrhosis progression; decompensation; fibrosis; HCC; modelling; natural history; outcomes; remission
Abstract
A sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA 24 weeks after withdrawal from therapy (SVR-24w), is the primary endpoint of antiviral therapy in chronic hepatitis C. There is solid evidence that patients who reach this target will remain virus free during long-term follow-up, with a risk of late HCV recurrence of <2% in published series using the most stringent criteria for assessing the virological response during and after antiviral therapy. Long-term observational studies indicate that SVR-24w has a profound impact on the natural course of chronic hepatitis C in relation to biochemical and histological remission of liver disease and improvement in quality of life. The effects of successful antiviral therapy on clinical endpoints such as the development of end-stage liver disease, its severe complications and liver-related mortality have been more difficult to ascertain because of the heterogeneity of the initial staging and rate of progression of chronic hepatitis C. However, most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival, at least in successfully treated patients who have already progressed to significant liver fibrosis or early cirrhosis. Outcome modelling suggests that these effects might also include HCV patients treated with milder forms of liver damage.
The primary endpoint of antiviral therapy for chronic hepatitis C is achieving sustained virological response (SVR), defined as undetectable hepatitis C virus (HCV)-RNA in serum 24 weeks after stopping antiviral therapy (SVR-24w). This is the endpoint used in all clinical trials to assess therapeutic interventions as well as by clinicians treating patients. This is because a large body of evidence exists that SVR-24w is an excellent surrogate endpoint to identify a permanent virological cure in most patients, with a clear clinical benefit in many of them. While it has been fairly easy to show that SVR-24w is associated with an extremely low risk of persistent HCV or recurrence during longer follow-up, data on the impact of SVR for more specific clinical endpoints have been limited by the heterogeneity of the initial presentation and rate and speed of chronic hepatitis C disease progression.
It is clear from studies on the natural history of HCV that a minority of patients with chronic infection develop significant life-long clinical complications, and it is also well known that current clinical practice has extended the indication to start antiviral therapy to patients with the mild or moderate hepatitis C, whose risk of progression is often difficult to define. When these patients receive antiviral therapy, data show that SVR improves quality of life and reduces the risk of histological progression. Although there is no direct evidence, outcome modelling suggests that there may be significant effects on clinical complications and survival in a subgroup of patients at risk of more rapid disease progression. On the other hand, solid evidence shows that the risk of developing end-stage liver disease, portal hypertension and hepatocellular carcinoma (HCC) is reduced in patients with more advanced liver disease or cirrhosis who achieve SVR with antiviral therapy.
In this chapter, we briefly discuss the data on the impact of SVR on long-term HCV eradication as well as on biochemical, histological and clinical outcomes in patients with hepatitis C depending on the phase of liver disease when therapy was begun.
Sustained virological response and long-term eradication of hepatitis C virus
There is good evidence that HCV permanently disappears from serum when antiviral therapy is successful. Most experts consider this to be the expression of complete and permanent viral eradication, while data on a persistent occult form of HCV in the liver and/or peripheral blood mononuclear cells (PBMC) are not fully convincing. Because HCV-RNA may be negative in serum during and at the end of antiviral therapy and reactivate after treatment withdrawal in a subgroup of patients with incomplete clearance (relapsers), viral negativity must be confirmed during off-therapy follow-up to confirm a definitive cure of hepatitis C. SVR is the primary goal of antiviral therapy in chronic hepatitis C and is classically defined as the absence, by the most sensitive polymerase chain reaction assay, of HCV-RNA in serum, 24 weeks after therapy has been withdrawn (SVR-24w) (1). This has been the definition since standard interferon (IFN) monotherapy was implemented and remained valid for IFN plus ribavirin combination therapy and more recently for pegylated interferon (PEG-IFN) plus ribavirin combination regimens. The SVR-24w definition of response to therapy will be maintained when new strategies of HCV treatment, including direct antiviral agents, are introduced into clinical practice. Indeed, most published studies as well as extensive clinical experience show that an absence of HCV-RNA in serum 6 months after therapy is the best indicator of HCV clearance, whatever the HCV genotype, patient characteristics, type and duration of treatment. This has been confirmed in several studies evaluating the long-term virological profile in large cohorts of patients treated with different schedules of IFN-based therapies and tested for HCV recurrence several months or years after having achieved SVR-24w.
Recently, Welker and Zeuzem (2) reviewed available data on the rates of late virological relapse in hepatitis C patients treated with IFN (or PEG-IFN) therapy with a sustained response based on the 24 week off-therapy rule. The authors identified 44 studies, including more than 4200 patients who had been followed up to 108 months after the end of therapy. Overall, late virological relapses were rare (3%). There was considerable heterogeneity among the different studies, with some of the smaller series reporting the highest rates of HCV recurrence. On the other hand, the larger series and those with the most stringent criteria to define SVR conclude that negative HCV-RNA in serum 24 weeks after the end of therapy is associated with a durable response and no recurrence of HCV during follow-up in more than 98% of cases.
Some studies have suggested that HCV-RNA may persist in the liver and/or in PBMC in patients who achieve SVR after antiviral therapy and with undetectable HCV-RNA in serum (3, 4). The significance of these findings is uncertain but most available data suggest that they are not clinically significant, at least in the immunocompetent host.
Thus, patients achieving SVR-24w with antiviral therapy can be considered clinically cured of viral infection, with an extremely low risk of late virological recurrence. If this occurs, reinfection rather than a ‘true’ relapse could be suspected and should be evaluated carefully.
Recently, it has been proposed that a 12-week post-treatment follow-up might be as relevant as 24 weeks to determine the sustained virological response in patients with hepatitis C virus receiving PEG-IFN and ribavirin (5).
Biochemical outcomes after sustained virological response
Alanine transaminase (ALT)/aspartate aminotransferase (AST) levels markedly improve in most patients who achieve SVR with antiviral therapy and permanently normalize in many (6, 7). The mean ALT and AST activities after therapy are significantly lower than the pretreatment baseline levels even in HCV carriers who began antiviral therapy with ‘normal’ ALT levels (8). Indeed, eradication of HCV by antiviral therapy in these cases is associated with a significant improvement in liver enzyme levels, which decrease from pretreatment ‘high normal’ to post-treatment ‘low normal’ levels. These findings suggest the presence of ongoing marginal liver disease activity even in HCV carriers with ‘normal’ range ALT levels, in agreement with histological findings of inflammation and fibrosis in around 15–25% of these patients (9).
On the other hand, liver enzymes may not normalize completely in patients with cirrhosis who achieve SVR. The discrepancy between biochemical and virological outcomes does not exclude a clinical benefit and is probably a sign of profound irreversible changes in hepatocyte metabolism from advanced cirrhosis.
As a general rule, other causes of liver damage (coinfections, alcohol, drugs, metabolic abnormalities) should be investigated in patients who achieve SVR with antiviral therapy but still have elevated ALT and/or AST.
Histological outcomes after sustained virological response
Many studies have described the histological outcome following antiviral therapy for chronic hepatitis C and have clearly identified some major differences among non-responders, partial responders, relapsers and sustained responders (10–15). Although the benefit to disease activity and progression with a partial or a transient virological response remains controversial, these studies clearly confirm that SVR is associated with histological improvement in disease activity and associated fibrosis. Liver steatosis is also improved when it is directly linked to HCV as for HCV-3.
The type and degree of histological benefit after SVR is highly dependent on pretreatment activity, the stage of liver disease and the interval between end of therapy and liver biopsy. Improvement in liver inflammation is more evident when a liver biopsy is obtained years rather than months after the end of therapy. The effect of time is even more evident for the regression of liver fibrosis. Available studies indicate that liver inflammation resolves in most, if not all, patients after SVR while improvement in fibrosis (regression) is found in 25–80%, worsening (progression) in only 0–12, and 16–68% remain stable. These results are significantly different from those in patients who do not achieve SVR. Table 1 describes some studies that have evaluated histological outcome after SVR using paired liver biopsies before and at different intervals after antiviral therapy. Available cumulative data on progression to cirrhosis have indicated that the risk after 1–10 years is reduced from 7–10% in non-responders to 0.5–1% in sustained responders, although it should be emphasized that patients who achieve SVR might have a milder and less progressive form of liver disease compared with non-responders.
Reversal of histological cirrhosis has been reported in patients achieving SVR with antiviral therapy. Although in most patients the benefit was limited to regression to METAVIR stage 3, i.e. advanced fibrosis with bridging, a histological sampling error cannot be excluded, other patients have been shown to achieve more marked and permanent histological benefit with regression from signs of cirrhosis to minimal-mild fibrosis.
Recent non-invasive markers of liver fibrosis, such as the FibroTest and FibroScan, have become important new tools for the management of patients with chronic hepatitis C. Results in patients receiving antiviral therapy have confirmed a marked improvement in liver fibrosis indexes following SVR (16, 17). Further validation for the optimized use of these methods during and after antiviral therapy is ongoing in several centres.
Sustained virological response and clinical outcomes
Morbidity and mortality in chronic hepatitis C infection are mainly associated with the complications of cirrhosis and the development of HCC, as well as an increased risk in liver-related deaths. It is therefore essential to assess the impact of SVR on these clinical outcomes. Because of the heterogeneity of the clinical presentation of chronic HCV infection, the slow and unpredictable progression and the lack of longitudinal studies of adequate size and duration, the impact of antiviral therapy and SVR on liver-related complications and mortality has been difficult to determine, especially in patients with milder forms of HCV-related liver disease. Although the endpoint of SVR is clearly associated with reduced histological disease progression in these patients, there is no clear evidence that this will result in reduced morbidity and mortality. At present, many patients with mild chronic hepatitis C are treated with antiviral therapy, especially younger patients or those infected with easy to clear HCV genotypes.
High SVR rates are achieved in these patients and outcome modelling also suggests that successful antiviral therapy could reduce the clinical burden of their disease. On the other hand, there are also convincing results associating a marked improvement in quality of life with SVR after antiviral therapy. This effect is largely independent of the stage of disease when treatment is begun (18). The clinical benefit associated with HCV clearance at any stage of chronic HCV infection is supported by recent results in a large population-based survey by Omland and Krarup (19), showing that overall life-long mortality as well as liver-and HCC-related mortality were significantly lower in HCV patients who showed a clearance of viraemia than in those with chronic viraemia.
Unlike the data for patients with milder forms of chronic hepatitis C, several studies have clearly shown that antiviral therapy with SVR is associated with a marked improvement in clinical outcomes in patients with advanced fibrosis or compensated cirrhosis. Indeed, most studies show that ascites, hepatic encephalopathy, jaundice or gastrointestinal bleeding are extremely rare after SVR has been achieved. Development of hepatocellular carcinoma is also significantly reduced, but patients with cirrhosis who clear HCV during antiviral therapy are still at a risk of developing HCC. Although the risk is certainly much lower than in age/gender/race-matched patients with active disease, continued monitoring is recommended. One of the most recent reports on the impact of combination PEG-IFN and ribavirin therapy on clinical outcome and complications in patients with chronic hepatitis C and advanced fibrosis is that of Cardoso et al. (20). These authors describe long-term outcomes in 307 patients with chronic hepatitis C and advanced fibrosis (127 cases) or cirrhosis (180 cases) treated with PEG-IFN plus ribavirin and followed up for a mean 3–5 years after treatment. SVR-24w was found in 33% of the cases, with no significant differences between patients with advanced fibrosis (37%) and cirrhosis (30%). During follow-up, the incidence of liver-related complications, HCC and liver-related deaths per 100 person – years was 0.63, 1.24 and 0.61, respectively, in patients with SVR and 4.16, 5.85 and 3.66, respectively, in patients without SVR. The difference for each outcome was statistically significant (P<0.001 by log-rank test). Multivariate analysis confirmed that SVR protected against progression to liver complications, HCC and liver-related deaths, with the relative risk in the absence of SVR ranging between 3.06 and 4.73. These results confirm those of several previous studies based on cohorts of patients treated with standard IFN, standard IFN plus ribavirin or PEG-IFN plus ribavirin, showing that antiviral treatment provides a definitive clinical advantage to patients with compensated cirrhosis who tolerate treatment and achieve an SVR.
Another recent study published by Bruno et al. (21) reported the effect of antiviral therapy and SVR on portal hypertension in HCV patients with cirrhosis. The authors reported results in 218 patients with cirrhosis who were untreated or treated with IFN-α-based therapy and followed up for a median 11.4 years. All patients had compensated cirrhosis when therapy began without oesophageal varices. Endoscopic monitoring was performed at 3-year intervals. None of the patients who achieved SVR developed oesophageal varices during follow-up compared with 32% of untreated patients and 39% of treated patients who did not achieve SVR, showing that SVR clinically improved the development of portal hypertension.
In conclusion, SVR improves the clinical outcomes in patients with chronic hepatitis C and advanced fibrosis or compensated cirrhosis. On the other hand, most studies assessing whether a partial response or long-term maintenance therapy with PEG-IFN without viral eradication is beneficial have failed to demonstrate any significant improvement in clinical outcomes (22, 23).
Conflicts of interest
The author has declared no potential conflicts.
References
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2 Welker MW, Zeuzem S. Occult hepatitis C: how convincing are the current data? Hepatology 2009; 49: 665–75.
3 Bartolomé J, López-Alcorocho JM, Castillo I, et al. Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C. J Virol 2007; 81: 7710–5.
4 Radkowski M, Horban A, Gallegos-Orozco JF, et al. Evidence for viral persistence in patients who test positive for anti-hepatitis C virus antibodies and have normal alanine aminotransferase levels. J Infect Dis 2005; 191: 1730–3.
5 Martinot-Peignoux M, Stern C, Maylin S, et al. Twelve weeks posttreatment follow-up is as relevant as 24 weeks to determine the sustained virologic response in patients with hepatitis C virus receiving pegylated interferon and ribavirin. Hepatology 2010; 51: 1122–6.
6 Chavalitdhamrong D, Tanwandee T. Long term out-comes of chronic hepatitis C patients with sustained virological response at 6 months after the end of treatment. World J Gastroenterol 2006; 12: 5532–5.
7 Marcellin P, Boyer N, Gervais A, et al. Long-tem histological improvement and loss of detectable intrahepatic HC RNA in patients with chronic hepatitis C and sustained response to interferon alfa therapy. Ann Int Med 1997; 127: 875–81.
8 Zeuzem S, Diago M, PEGASYS Study NR16071 Investigator Group et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004; 127: 1724–32.
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16 Poynard T, Ngo Y, Munteanu M, et al. Biomarkers of liver injury for hepatitis clinical trials: a meta-analysis of longitudinal studies. Antivir Ther 2010; 15: 617–31.
17 Wang JH, Changchien CS, Hung CH, et al. Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: longitudinal study using FibroScan. J Gastroenterol Hepatol 2010; 25: 964–9.
18 Arora S, O'Brien C, Zeuzem S, et al. Treatment of chronic hepatitis C patients with persistently normal alanine aminotransferase levels with the combination of peginterferon alpha-2a (40 kDa) plus ribavirin: impact on health-related quality of life. J Gastroenterol Hepatol 2006; 21: 406–12.
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23 Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359: 2429–41.
Source
January 26, 2011
How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy?
Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 13–17, January 2011
Laurent Castera 1, Pierre Bedossa 2
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Hepatology, Hôpital St André & Haut Lévêque, Bordeaux University Hospital, Bordeaux, France
2 Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, INSERM, Paris-Diderot University, Paris, France
* Correspondence: Correspondence Laurent Castera, MD, PhD, Service d' Hépatologie, Hǒpital Beaujon, Assistance Publique Hǒpitaux de Paris, 100 Boulevard du Général Leclerc, 92110 Clichy, France Tel: +33 5 57 65 64 39 Fax: +33 5 57 65 64 45 e-mail: laurent.castera@chu-bordeaux.fr
Keywords:
FibroScan; liver biopsy; liver fibrosis; non-invasive; serum biomarkers; transient elastography
Abstract
The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a ‘biological’ approach based on the dosage of serum biomarkers of fibrosis; (ii) a ‘physical’ approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.
Liver fibrosis is a result of excessive extracellular matrix deposition in the liver in response to chronic inflammatory injury triggered by persistent hepatitis C virus in the liver. Hepatic fibrosis is determined by the replication balance between fibrogenesis and fibrosis degradation. When this balance favours fibrogenesis, there is a resulting accumulation of collagen and extracellular matrix, leading eventually to cirrhosis. Liver fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality in patients with hepatitis C virus (HCV) infection (1, 2). Besides the development of antiviral drugs, there are intensive efforts to develop drugs to effectively target the mechanism of fibrogenesis or to eliminate fibrous tissue once it has accumulated in the liver (3). Therefore, the assessment of liver fibrosis is a major issue in the management of patients with chronic HCV infection (4, 5).
Liver biopsy
For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.
However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.
Observer variation is another potential limitation of biopsy that is related to the difference between pathologist's interpretation of the biopsy (6, 9, 10). The use of histopathological scoring systems for the evaluation of fibrosis has limited this drawback and several studies have shown that agreement between pathologists is satisfactory, especially when the staging of fibrosis is performed by specialized liver pathologists (9, 10). Thus, although liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.
Because liver biopsy is invasive, the only serious limitations are the potential adverse effects and complications that have been comprehensively reviewed elsewhere (11). Transient and moderate pain along with anxiety and discomfort are common (12, 13). Severe complications such as haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has been reported occasionally for biopsies in advanced liver diseases, haemorrhagical tumours and in patients with major comorbidities. A biopsy via the transjugular route considerably reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy performed by a trained physician, limiting the number of passes and ultrasound guidance can significantly decrease the risk of complications, thus increasing the safety of biopsy. Nevertheless, a liver biopsy should be performed only after carefully balancing the risks of the procedure with the potential benefits in terms of patient management. Despite these limitations, liver biopsy provides invaluable information that none of the non-invasive markers provide. Although the evaluation of fibrosis is a major decision criterion for hepatologists, fibrosis is only one of the many elementary histopathological features present on liver biopsy. In effect, fibrosis is not an autonomous feature, but scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophical processes. The simultaneous evaluation of necroinflammation (portal tract inflammation, interface hepatitis, lobular inflammation) shows whether fibrosis is the result of a past event that has stabilized or even regressed or is an ongoing process that may continue to worsen. Associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis, can also frequently be detected with biopsy (14).
Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.
Non-invasive methods for the assessment of liver fibrosis
There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).
Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with TE are the aspartate-to-platelet ratio index (APRI) (a free non-patented index) and the FibroTest (21, 22, 23).
The results of TE and serum biomarkers for the diagnosis of significant fibrosis have been shown to be equivalent in patients with chronic hepatitis C infection (24, 25). Indeed, in the largest study to date (n=1307) (25), comparing TE with several patented and non-patented biomarkers (FibroTest, Fibrometre, Hepascore and APRI) and using liver biopsy as a reference, the AUROCs of TE (0.76) did not differ from those of serum biomarkers (0.72–0.78).
In order to increase the diagnostic accuracy of these tests, the sequential combination of biomarkers (26, 27) or the concomitant combination of TE and biomarkers (24, 28, 29) has been proposed. The latter strategy may be more effective for diagnosing significant fibrosis, leading to a reduction in the use of liver biopsy in more than 70% of cases compared with 50% when using biomarkers (APRI and FibroTest) sequentially (30). Another advantage of combining two unrelated methods such as TE and biomarkers rather than two biomarkers is that TE provides a more direct measurement of liver structure than biomarkers and there is no relationship between the applicability of TE and biomarkers such as the FibroTest (28).
For the diagnosis of cirrhosis, the situation is different because TE appears to be the most accurate method compared with currently available biomarkers and routine blood tests, preventing the need for a liver biopsy in around 90% of cases (25, 31). As a result, a combination of both methods does not seem to increase the diagnostic accuracy (30).
Limitations of non-invasive methods
Serum markers
Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).
Transient elastography
Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.
Finally, because the liver is an organ wrapped in an expandable but non-elastic envelope (Glisson's capsula), additional space-occupying tissue abnormalities independent of fibrosis, such as oedema and inflammation, cholestasis and congestion, may interfere with LSM. The risk of overestimating liver stiffness values has been reported in the case of alanine aminotransferase flares in patients with acute viral hepatitis or chronic hepatitis B (38, 39, 40) as well as in cases of extrahepatic cholestasis (41) or congestive heart failure (42).
How to use liver biopsy and non-invasive methods in clinical practice?
A liver biopsy should be performed in the case of comorbidities such as alcoholism or metabolic syndrome when non-invasive methods cannot be used or in any unclear situation such as discordant results of non-invasive tests. Conversely, liver biopsy should not be performed when the clinical diagnosis is obvious (cirrhosis) or when no benefit can be expected from the biopsy for patient management. Although there is no optimal threshold, the longer the specimen, the more accurate the staging will be (43). A 20–25 mm long biopsy is considered optimal although a robust evaluation is often possible on a 15 mm long biopsy. Ideally, the biopsy should be read by an experienced liver pathologist because it decreases the source of variability in the histological interpretation (44).
In naïve patients without comorbidities who are candidates for antiviral treatment, non-invasive tests can be used for the first-line staging of fibrosis. The use of either TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities (45). However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable. For instance, when there is a strong clinical suspicion of cirrhosis, in most cases the use of TE is enough to confirm the diagnosis without a liver biopsy. Conversely, a liver biopsy may be necessary to differentiate between F1 and F2 in genotype 1-infected patients before making a decision on antiviral treatment. In the same way, a liver biopsy may be useful to differentiate between F3 and F4 when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments (46, 47), differentiating between F1 and F2 may not be as important for treatment indications.
When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.
Finally, non-invasive methods can be of interest in the follow-up of untreated patients (48). Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis.
Conclusion and perspectives
There is an urgent need to pursue the development of non-invasive tests in addition to a liver biopsy for the staging of fibrosis. Because of the conditional relationship with biopsy, the development of serum markers will always have obvious limitations. Promising preliminary results suggest that novel alternative imaging techniques such as magnetic resonance elastography, acoustic radiation force impulse imaging or perfusion computed tomography will eventually be refined to reach an acceptable level of accuracy, especially for the evaluation of early and intermediate stages of fibrosis (49–51). These might become less pertinent as antiviral treatments become more efficient, with fewer side effects.
Conflicts of interest
The authors have declared no potential conflicts.
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9 Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994; 20: 15–20.
10 Goldin RD, Goldin JG, Burt AD, et al. Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis. J Hepatol 1996; 25: 649–54.
11 Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000; 32: 477–81.
12 Castera L, Negre I, Samii K, et al. Pain experienced during percutaneous liver biopsy. Hepatology 1999; 30: 1529–30.
13 Castera L, Negre I, Samii K, et al. Patient-administered nitrous oxide/oxygen inhalation provides safe and effective analgesia for percutaneous liver biopsy: a randomized placebo-controlled trial. Am J Gastroenterol 2001; 96: 1553–7.
14 Bedossa P, Moucari R, Chelbi E, et al. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology 2007; 46: 380–7.
15 Saadeh S, Cammell G, Carey WD, et al. The role of liver biopsy in chronic hepatitis C. Hepatology 2001; 33: 196–200.
16 Castera L, Pinzani M. Non-invasive assessment of liver fibrosis: are we ready? Lancet 2010; 375: 1419–20.
17 Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatol 2009; 50: 1–3.
18 Pinzani M, Vizzutti F, Arena U, et al. Technology Insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol 2008; 5: 95–106.
19 Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008; 134: 1670–81.
20 Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? Gut 2010; 59: 861–6.
21 Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134: 960–74.
22 Poynard T, Morra R, Halfon P, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007; 7: 40.
23 Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. Hepatology 2007; 46: 912–21.
24 Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128: 343–50.
25 Degos F, Perez P, Roche B, et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol 2010; 53: 1013–21.
26 Sebastiani G, Vario A, Guido M, et al. Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C. J Hepatol 2006; 44: 686–93.
27 Sebastiani G, Halfon P, Castera L, et al. SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology 2009; 49: 1821–7.
28 Poynard T, Ingiliz P, Elkrief L, et al. Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers. PLoS ONE 2008; 3: e3857.
29 Boursier J, Vergniol J, Sawadogo A, et al. The combination of a blood test and FibroScan improves the non-invasive diagnosis of liver fibrosis. Liver Int 2009; 29: 1507–15.
30 Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol 2010; 52: 191–8.
31 Castera L, Le Bail B, Roudot-Thoraval F, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009; 50: 59–68.
32 Imbert-Bismut F, Messous D, Thibaut V, et al. Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors. Clin Chem Lab Med 2004; 42: 323–33.
33 Cales P, Veillon P, Konate A, et al. Reproducibility of blood tests of liver fibrosis in clinical practice. Clin Biochem 2008; 41: 10–8.
34 Poynard T, Munteanu M, Imbert-Bismut F, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clin Chem 2004; 50: 1344–55.
35 Fraquelli M, Rigamonti C, Casazza G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007; 56: 968–73.
36 Boursier J, Konate A, Gorea G, et al. Reproducibility of liver stiffness measurement by ultrasonographic elastometry. Clin Gastroenterol Hepatol 2008; 6: 1263–9.
37 Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13 369 examinations. Hepatology 2010; 51: 828–35.
38 Coco B, Oliveri F, Maina AM, et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007; 14: 360–9.
39 Sagir A, Erhardt A, Schmitt M, et al. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2007; 47: 592–5.
40 Arena U, Vizzutti F, Corti G, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008; 47: 380–4.
41 Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008; 48: 1718–23.
42 Millonig G, Friedrich S, Adolf S, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010; 52: 206–10.
43 Scheuer PJ. Liver biopsy size matters in chronic hepatitis: bigger is better. Hepatology 2003; 38: 1356–8.
44 Rousselet MC, Michalak S, Dupre F, et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology 2005; 41: 257–64.
45 Non invasive methods for the evaluation of hepatic fibrosis/cirrhosis: an update, 2008. Available at http://www.has-sante.fr/
46 Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.
47 Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705–16.
48 Hézode C, Castéra L, Rosa I, et al. Prospective evaluation of liver stiffness dynamics during and after peginterferon alpha-ribavirin treatment in patients with chronic hepatitis C (abstract). Hepatology 2008; 48 (Suppl.): 849A.
49 Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135: 32–40.
50 Friedrich-Rust M, Wunder K, Kriener S, et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 2009; 252: 595–604.
51 Ronot M, Asselah T, Paradis V, et al. Liver fibrosis in chronic hepatitis C virus infection: differentiating minimal from intermediate fibrosis with perfusion CT. Radiology 2010; 256: 135–42.
Source
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 13–17, January 2011
Laurent Castera 1, Pierre Bedossa 2
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Hepatology, Hôpital St André & Haut Lévêque, Bordeaux University Hospital, Bordeaux, France
2 Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, INSERM, Paris-Diderot University, Paris, France
* Correspondence: Correspondence Laurent Castera, MD, PhD, Service d' Hépatologie, Hǒpital Beaujon, Assistance Publique Hǒpitaux de Paris, 100 Boulevard du Général Leclerc, 92110 Clichy, France Tel: +33 5 57 65 64 39 Fax: +33 5 57 65 64 45 e-mail: laurent.castera@chu-bordeaux.fr
Keywords:
FibroScan; liver biopsy; liver fibrosis; non-invasive; serum biomarkers; transient elastography
Abstract
The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a ‘biological’ approach based on the dosage of serum biomarkers of fibrosis; (ii) a ‘physical’ approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.
Liver fibrosis is a result of excessive extracellular matrix deposition in the liver in response to chronic inflammatory injury triggered by persistent hepatitis C virus in the liver. Hepatic fibrosis is determined by the replication balance between fibrogenesis and fibrosis degradation. When this balance favours fibrogenesis, there is a resulting accumulation of collagen and extracellular matrix, leading eventually to cirrhosis. Liver fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality in patients with hepatitis C virus (HCV) infection (1, 2). Besides the development of antiviral drugs, there are intensive efforts to develop drugs to effectively target the mechanism of fibrogenesis or to eliminate fibrous tissue once it has accumulated in the liver (3). Therefore, the assessment of liver fibrosis is a major issue in the management of patients with chronic HCV infection (4, 5).
Liver biopsy
For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.
However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.
Observer variation is another potential limitation of biopsy that is related to the difference between pathologist's interpretation of the biopsy (6, 9, 10). The use of histopathological scoring systems for the evaluation of fibrosis has limited this drawback and several studies have shown that agreement between pathologists is satisfactory, especially when the staging of fibrosis is performed by specialized liver pathologists (9, 10). Thus, although liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.
Because liver biopsy is invasive, the only serious limitations are the potential adverse effects and complications that have been comprehensively reviewed elsewhere (11). Transient and moderate pain along with anxiety and discomfort are common (12, 13). Severe complications such as haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has been reported occasionally for biopsies in advanced liver diseases, haemorrhagical tumours and in patients with major comorbidities. A biopsy via the transjugular route considerably reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy performed by a trained physician, limiting the number of passes and ultrasound guidance can significantly decrease the risk of complications, thus increasing the safety of biopsy. Nevertheless, a liver biopsy should be performed only after carefully balancing the risks of the procedure with the potential benefits in terms of patient management. Despite these limitations, liver biopsy provides invaluable information that none of the non-invasive markers provide. Although the evaluation of fibrosis is a major decision criterion for hepatologists, fibrosis is only one of the many elementary histopathological features present on liver biopsy. In effect, fibrosis is not an autonomous feature, but scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophical processes. The simultaneous evaluation of necroinflammation (portal tract inflammation, interface hepatitis, lobular inflammation) shows whether fibrosis is the result of a past event that has stabilized or even regressed or is an ongoing process that may continue to worsen. Associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis, can also frequently be detected with biopsy (14).
Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.
Non-invasive methods for the assessment of liver fibrosis
There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).
Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with TE are the aspartate-to-platelet ratio index (APRI) (a free non-patented index) and the FibroTest (21, 22, 23).
The results of TE and serum biomarkers for the diagnosis of significant fibrosis have been shown to be equivalent in patients with chronic hepatitis C infection (24, 25). Indeed, in the largest study to date (n=1307) (25), comparing TE with several patented and non-patented biomarkers (FibroTest, Fibrometre, Hepascore and APRI) and using liver biopsy as a reference, the AUROCs of TE (0.76) did not differ from those of serum biomarkers (0.72–0.78).
In order to increase the diagnostic accuracy of these tests, the sequential combination of biomarkers (26, 27) or the concomitant combination of TE and biomarkers (24, 28, 29) has been proposed. The latter strategy may be more effective for diagnosing significant fibrosis, leading to a reduction in the use of liver biopsy in more than 70% of cases compared with 50% when using biomarkers (APRI and FibroTest) sequentially (30). Another advantage of combining two unrelated methods such as TE and biomarkers rather than two biomarkers is that TE provides a more direct measurement of liver structure than biomarkers and there is no relationship between the applicability of TE and biomarkers such as the FibroTest (28).
For the diagnosis of cirrhosis, the situation is different because TE appears to be the most accurate method compared with currently available biomarkers and routine blood tests, preventing the need for a liver biopsy in around 90% of cases (25, 31). As a result, a combination of both methods does not seem to increase the diagnostic accuracy (30).
Limitations of non-invasive methods
Serum markers
Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).
Transient elastography
Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.
Finally, because the liver is an organ wrapped in an expandable but non-elastic envelope (Glisson's capsula), additional space-occupying tissue abnormalities independent of fibrosis, such as oedema and inflammation, cholestasis and congestion, may interfere with LSM. The risk of overestimating liver stiffness values has been reported in the case of alanine aminotransferase flares in patients with acute viral hepatitis or chronic hepatitis B (38, 39, 40) as well as in cases of extrahepatic cholestasis (41) or congestive heart failure (42).
How to use liver biopsy and non-invasive methods in clinical practice?
A liver biopsy should be performed in the case of comorbidities such as alcoholism or metabolic syndrome when non-invasive methods cannot be used or in any unclear situation such as discordant results of non-invasive tests. Conversely, liver biopsy should not be performed when the clinical diagnosis is obvious (cirrhosis) or when no benefit can be expected from the biopsy for patient management. Although there is no optimal threshold, the longer the specimen, the more accurate the staging will be (43). A 20–25 mm long biopsy is considered optimal although a robust evaluation is often possible on a 15 mm long biopsy. Ideally, the biopsy should be read by an experienced liver pathologist because it decreases the source of variability in the histological interpretation (44).
In naïve patients without comorbidities who are candidates for antiviral treatment, non-invasive tests can be used for the first-line staging of fibrosis. The use of either TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities (45). However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable. For instance, when there is a strong clinical suspicion of cirrhosis, in most cases the use of TE is enough to confirm the diagnosis without a liver biopsy. Conversely, a liver biopsy may be necessary to differentiate between F1 and F2 in genotype 1-infected patients before making a decision on antiviral treatment. In the same way, a liver biopsy may be useful to differentiate between F3 and F4 when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments (46, 47), differentiating between F1 and F2 may not be as important for treatment indications.
When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.
Finally, non-invasive methods can be of interest in the follow-up of untreated patients (48). Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis.
Conclusion and perspectives
There is an urgent need to pursue the development of non-invasive tests in addition to a liver biopsy for the staging of fibrosis. Because of the conditional relationship with biopsy, the development of serum markers will always have obvious limitations. Promising preliminary results suggest that novel alternative imaging techniques such as magnetic resonance elastography, acoustic radiation force impulse imaging or perfusion computed tomography will eventually be refined to reach an acceptable level of accuracy, especially for the evaluation of early and intermediate stages of fibrosis (49–51). These might become less pertinent as antiviral treatments become more efficient, with fewer side effects.
Conflicts of interest
The authors have declared no potential conflicts.
References
1 Khan MH, Farrell GC, Byth K, et al. Which patients with hepatitis C develop liver complications? Hepatology 2000; 31: 513–20.
2 Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002; 36 (Suppl. 1): S47–56.
3 Talwalkar JA. Antifibrotic therapies – emerging biomarkers as treatment end points. Nat Rev Gastroenterol Hepatol 2010; 7: 59–61.
4 Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR cooperative study group. Hepatology 1996; 24: 289–93.
5 Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696–9.
6 Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97: 2614–8.
7 Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003; 38: 1449–57.
8 Colloredo G, Guido M, Sonzogni A, et al. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003; 39: 239–44.
9 Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. The French METAVIR Cooperative Study Group. Hepatology 1994; 20: 15–20.
10 Goldin RD, Goldin JG, Burt AD, et al. Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis. J Hepatol 1996; 25: 649–54.
11 Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000; 32: 477–81.
12 Castera L, Negre I, Samii K, et al. Pain experienced during percutaneous liver biopsy. Hepatology 1999; 30: 1529–30.
13 Castera L, Negre I, Samii K, et al. Patient-administered nitrous oxide/oxygen inhalation provides safe and effective analgesia for percutaneous liver biopsy: a randomized placebo-controlled trial. Am J Gastroenterol 2001; 96: 1553–7.
14 Bedossa P, Moucari R, Chelbi E, et al. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology 2007; 46: 380–7.
15 Saadeh S, Cammell G, Carey WD, et al. The role of liver biopsy in chronic hepatitis C. Hepatology 2001; 33: 196–200.
16 Castera L, Pinzani M. Non-invasive assessment of liver fibrosis: are we ready? Lancet 2010; 375: 1419–20.
17 Bedossa P, Carrat F. Liver biopsy: the best, not the gold standard. J Hepatol 2009; 50: 1–3.
18 Pinzani M, Vizzutti F, Arena U, et al. Technology Insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol 2008; 5: 95–106.
19 Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008; 134: 1670–81.
20 Castera L, Pinzani M. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? Gut 2010; 59: 861–6.
21 Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008; 134: 960–74.
22 Poynard T, Morra R, Halfon P, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007; 7: 40.
23 Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of hepatitis C-related fibrosis: a systematic review. Hepatology 2007; 46: 912–21.
24 Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005; 128: 343–50.
25 Degos F, Perez P, Roche B, et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol 2010; 53: 1013–21.
26 Sebastiani G, Vario A, Guido M, et al. Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C. J Hepatol 2006; 44: 686–93.
27 Sebastiani G, Halfon P, Castera L, et al. SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology 2009; 49: 1821–7.
28 Poynard T, Ingiliz P, Elkrief L, et al. Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers. PLoS ONE 2008; 3: e3857.
29 Boursier J, Vergniol J, Sawadogo A, et al. The combination of a blood test and FibroScan improves the non-invasive diagnosis of liver fibrosis. Liver Int 2009; 29: 1507–15.
30 Castera L, Sebastiani G, Le Bail B, et al. Prospective comparison of two algorithms combining non-invasive methods for staging liver fibrosis in chronic hepatitis C. J Hepatol 2010; 52: 191–8.
31 Castera L, Le Bail B, Roudot-Thoraval F, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol 2009; 50: 59–68.
32 Imbert-Bismut F, Messous D, Thibaut V, et al. Intra-laboratory analytical variability of biochemical markers of fibrosis (Fibrotest) and activity (Actitest) and reference ranges in healthy blood donors. Clin Chem Lab Med 2004; 42: 323–33.
33 Cales P, Veillon P, Konate A, et al. Reproducibility of blood tests of liver fibrosis in clinical practice. Clin Biochem 2008; 41: 10–8.
34 Poynard T, Munteanu M, Imbert-Bismut F, et al. Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C. Clin Chem 2004; 50: 1344–55.
35 Fraquelli M, Rigamonti C, Casazza G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007; 56: 968–73.
36 Boursier J, Konate A, Gorea G, et al. Reproducibility of liver stiffness measurement by ultrasonographic elastometry. Clin Gastroenterol Hepatol 2008; 6: 1263–9.
37 Castera L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13 369 examinations. Hepatology 2010; 51: 828–35.
38 Coco B, Oliveri F, Maina AM, et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat 2007; 14: 360–9.
39 Sagir A, Erhardt A, Schmitt M, et al. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2007; 47: 592–5.
40 Arena U, Vizzutti F, Corti G, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008; 47: 380–4.
41 Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008; 48: 1718–23.
42 Millonig G, Friedrich S, Adolf S, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010; 52: 206–10.
43 Scheuer PJ. Liver biopsy size matters in chronic hepatitis: bigger is better. Hepatology 2003; 38: 1356–8.
44 Rousselet MC, Michalak S, Dupre F, et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology 2005; 41: 257–64.
45 Non invasive methods for the evaluation of hepatic fibrosis/cirrhosis: an update, 2008. Available at http://www.has-sante.fr/
46 Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.
47 Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705–16.
48 Hézode C, Castéra L, Rosa I, et al. Prospective evaluation of liver stiffness dynamics during and after peginterferon alpha-ribavirin treatment in patients with chronic hepatitis C (abstract). Hepatology 2008; 48 (Suppl.): 849A.
49 Huwart L, Sempoux C, Vicaut E, et al. Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology 2008; 135: 32–40.
50 Friedrich-Rust M, Wunder K, Kriener S, et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 2009; 252: 595–604.
51 Ronot M, Asselah T, Paradis V, et al. Liver fibrosis in chronic hepatitis C virus infection: differentiating minimal from intermediate fibrosis with perfusion CT. Radiology 2010; 256: 135–42.
Source
Advances in Chronic Hepatitis C Treatment And Liver Transplantation: An Update
ISSUE: JANUARY, 2011
VOLUME: 62:01
The Center for the Study of Hepatitis C (CSHC) at NewYork-Presbyterian/Weill Cornell Medical Center is engaged in diverse HCV investigations. One of us (Dr. Talal) has undertaken research on viral kinetics, presenting the first evaluation of pegIFN pharmacokinetics in patients coinfected with HCV and HIV, finding that, although pharmacokinetic parameters do not differentiate sustained virological responders from nonresponders, certain pharmaco - dynamic measurements do and might therefore serve as useful predictors of treatment outcome.
PDF Download: Advances in Chronic Hepatitis C Treatment And Liver Transplantation: An Update (Acrobat Reader is required)
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VOLUME: 62:01
The Center for the Study of Hepatitis C (CSHC) at NewYork-Presbyterian/Weill Cornell Medical Center is engaged in diverse HCV investigations. One of us (Dr. Talal) has undertaken research on viral kinetics, presenting the first evaluation of pegIFN pharmacokinetics in patients coinfected with HCV and HIV, finding that, although pharmacokinetic parameters do not differentiate sustained virological responders from nonresponders, certain pharmaco - dynamic measurements do and might therefore serve as useful predictors of treatment outcome.
PDF Download: Advances in Chronic Hepatitis C Treatment And Liver Transplantation: An Update (Acrobat Reader is required)
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Adult Stem Cells Treat End-Stage Liver Disease
January 26, 2011
A team of researchers in California and in Egypt report therapeutic benefit treating end-stage liver disease patients with adult stem cells A total of 48 patients were treated with their own adult stem cells–36 patients with chronic, end-stage hepatitis C-induced liver disease, and 12 patients with end-stage autoimmune liver disease. Researchers used the factor G-CSF, commonly used to mobilize bone marrow adult stem cells into the circulation, to obtain the cells from each patient. The CD34+ stem cells were then isolated, amplified to increase numbers of cells, partially differentiated in culture, then re-injected into each patient via their hepatic artery or portal vein. The results were published in Cell Transplantation
According to co-author Dr. Mark A. Zern of University of California-Davis Medical Center:
“This enabled us to transplant as many as one billion of these cells per patient. For all patients there was a statistically significant decrease in peritoneal cavity fluid, or ‘ascites’. There was also clinical and biochemical improvement in a large percentage of patients who received the transplantation. The finding of improvement in ascites in a significant number of patients is impressive and somewhat surprising, suggesting that cell transplantation might be clinically significant beyond the improvement in laboratory parameters.”
The mechanism by which the infusion of CD34+ adult stem cells improves liver function is still unclear. As to whether any partial differentiation into liver cells was needed for the therapeutic results, Dr. Stephen Strom at the University of Pittsburgh and section editor for Cell Transplantation, noted:
“Other research groups are now showing similar results with cells without any hepatic characteristics, including fractionated and unfractionated bone marrow and mesenchymal stem cells. Taken together, these data suggest that the positive effects these researchers find may be the result of paracrine effects from factors secreted by the donor cells.
Published data in 1999 suggested that some bone marrow adult stem cells could form liver hepatocytes. Others reported similar results in 2000 using mice, by observing liver cells of human bone marrow adult stem cell transplant patients, and in experiments showing regeneration of liver in mice. However, some published evidence also indicates that the regenerative capacity of bone marrow adult stem cells is due to paracrine effects, i.e., secreted factors.
No matter what the mechanism, various clinical trials are investigating use of adult stem cells for liver diseases. Published results from earlier trials show therapeutic benefit of adult stem cells for liver repair and regeneration.
In a published 2010 report, a Korean group found some improvement in liver cirrhosis patients using their own adult stem cells.
In 2006 a U.K. group reported improvement in patients with liver insufficiency treated with their own adult stem cells, and the same group reported in 2008 the long-term improvement of chronic liver disease patients, using the patients’ own adult stem cells in a trial similar to the current Egyptian trial.
Also in 2006, a German group reported increased liver regeneration in liver cancer patients using adult stem cells, and a Japanese team found improved liver function in cirrhosis patients after using the patients’ own bone marrow adult stem cells.
Adult stem cells continue to provide ethical and successful results for patients.
Source
January 25, 2011
An HIV Protein and Telomerase Inhibitor Join Forces Against Cancer
Posted on January 13, 2011 by Kristine Novak, PhD, Science Editor
Researchers have found a way to specifically kill liver cancer cells and stop tumor growth. In the January issue of Gastroenterology, Guangming Chen et al. report that fusion of a natural inhibitor of telomerase to an HIV protein stops proliferation of hepatocellular carcinoma (HCC) cells and growth of liver tumors in mice.
Cancer cells, especially HCC cells, overexpress the enzyme telomerase, which allows them to extend their chromosome ends and proliferate indefinitely. Telomerase has been investigated as an anti-cancer target because it is required for long-term proliferation of cancer cells and is inactive in most healthy cells. Chen et al. fused part of the protein LPTS—an endogenous blocker of telomerase—to the HIV Tat protein, which allowed the fusion protein (called TAT-LPTS-LC) to cross cell membranes and induce telomere shortening, cell crisis (white arrows in figure) and apoptosis of HCC cells (red arrows in figure). TAT-LPTS-LC also reduced the tumorigenicity of HCC cells in mice.
Chen et al. observed the inhibitory effects of TAT-LPTS-LC only in telomerase-positive cells—normal cells were not affected and the fusion protein caused no signs of toxicity in the mice. This might be because normal cells already express LPTS, whereas cancer cells lose it, which allows them to replicate indefinitely; LPTS is reduced or absent in 40%–50% of cases of HCC and other tumor samples.
LPTS (also called PinX1) was the first natural telomerase inhibitor identified. Chen et al. note that although TAT-LPTS-LC suppresses tumor growth effectively, its effects in mice took several weeks, rather than inducing an immediate response. Combinations of telomerase inhibitors and chemotherapeutic drugs might be used to reduce this lag phase and cause rapid and sustained tumor cell death.
Read the article online:
Chen G, Da L, Wang H, et al. HIV-tat–mediated delivery of an LPTS functional fragment inhibits telomerase activity and tumorigenicity of hepatoma cells. Gastroenterology 2011;140:332–343.
Source
Researchers have found a way to specifically kill liver cancer cells and stop tumor growth. In the January issue of Gastroenterology, Guangming Chen et al. report that fusion of a natural inhibitor of telomerase to an HIV protein stops proliferation of hepatocellular carcinoma (HCC) cells and growth of liver tumors in mice.
Cancer cells, especially HCC cells, overexpress the enzyme telomerase, which allows them to extend their chromosome ends and proliferate indefinitely. Telomerase has been investigated as an anti-cancer target because it is required for long-term proliferation of cancer cells and is inactive in most healthy cells. Chen et al. fused part of the protein LPTS—an endogenous blocker of telomerase—to the HIV Tat protein, which allowed the fusion protein (called TAT-LPTS-LC) to cross cell membranes and induce telomere shortening, cell crisis (white arrows in figure) and apoptosis of HCC cells (red arrows in figure). TAT-LPTS-LC also reduced the tumorigenicity of HCC cells in mice.
TAT-LPTS-LC shortens cancer cell telomeres
to induce cell crisis and apoptosis.
LPTS (also called PinX1) was the first natural telomerase inhibitor identified. Chen et al. note that although TAT-LPTS-LC suppresses tumor growth effectively, its effects in mice took several weeks, rather than inducing an immediate response. Combinations of telomerase inhibitors and chemotherapeutic drugs might be used to reduce this lag phase and cause rapid and sustained tumor cell death.
Read the article online:
Chen G, Da L, Wang H, et al. HIV-tat–mediated delivery of an LPTS functional fragment inhibits telomerase activity and tumorigenicity of hepatoma cells. Gastroenterology 2011;140:332–343.
Source
Fibrosis in Patients with HIV and Hepatitis C
Posted on December 16, 2010 by Kristine Novak, PhD, Science Editor
HIV infection does not speed the progression of fibrosis in patients with Hepatitis C, according to findings from Richard Sterling et al. in the December issue of Clinical Gastroenterology and Hepatology.
Sterling et al. compared liver biopsies taken from more than 300 patients with HIV/HCV co-infection and more than 200 with only HCV infection. They found that fibrosis progressed in 20% of HIV/HCV co-infected patients over time (10% by 1 stage and 10% by 2 or more stages)—this was not significantly different than progression in patients with only HCV infection (22%; 17% by 1 stage and 5% by 2 stages). Patients’ baseline features—such as inflammation or steatosis—were not associated with progression, nor were numbers of T cells, levels of HIV RNA, or any particular therapeutic regimen for HIV infection.
Previous studies reported that fibrosis progressed more rapidly in HIV/HCV co-infected patients, and that all co-infected patients—even those without significant liver damage—should receive anti-HCV therapy. However, most of these studies were either retrospective, based only on estimates of disease duration, or in patients that had received anti-HCV therapy, so disease progression was poorly defined. Before the study of Sterling et al., there were no direct comparisons of co-infected patients who were matched with patients with HCV alone.
Limitations to the study include referral bias and self-selection for subjects that were willing to undergo a second biopsy. Furthermore, the authors were not able to account for alcohol use between biopsies and did not have accurate data on alcohol use in those with HCV alone. Although Sterling et al. did not associate any particular anti-HIV therapy with fibrosis, the specific regimen for each patient was not controlled, and the authors did not account for compliance or change in anti-HIV therapies between biopsies.
The authors recommend that all co-infected patients be repeatedly assessed for disease severity by liver biopsy analyses at periodic intervals. Because a significant proportion of patients with HIV and HCV did not have increasing liver damage, decisions on whether to begin HCV therapy should depend on patient compliance and likelihood of response, rather than concerns about rapid disease progression. Sterling et al. conclude that it is reasonable to defer HCV therapy in patients with mild disease until better therapies for HCV are available.
Read a related review:
Price JC, Thio CL. Liver disease in the HIV-infected individual. Clin Gastroenterol and Hepatol 2010;8:1002–1012.
Read the complementary Gastroenterology article:
de Vries–Slujis TEMS, Reijnders JGP, Hansen BE, et al. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus. Gastroenterology 2010;139:1934–1941.
Source
HIV infection does not speed the progression of fibrosis in patients with Hepatitis C, according to findings from Richard Sterling et al. in the December issue of Clinical Gastroenterology and Hepatology.
Sterling et al. compared liver biopsies taken from more than 300 patients with HIV/HCV co-infection and more than 200 with only HCV infection. They found that fibrosis progressed in 20% of HIV/HCV co-infected patients over time (10% by 1 stage and 10% by 2 or more stages)—this was not significantly different than progression in patients with only HCV infection (22%; 17% by 1 stage and 5% by 2 stages). Patients’ baseline features—such as inflammation or steatosis—were not associated with progression, nor were numbers of T cells, levels of HIV RNA, or any particular therapeutic regimen for HIV infection.
Previous studies reported that fibrosis progressed more rapidly in HIV/HCV co-infected patients, and that all co-infected patients—even those without significant liver damage—should receive anti-HCV therapy. However, most of these studies were either retrospective, based only on estimates of disease duration, or in patients that had received anti-HCV therapy, so disease progression was poorly defined. Before the study of Sterling et al., there were no direct comparisons of co-infected patients who were matched with patients with HCV alone.
Limitations to the study include referral bias and self-selection for subjects that were willing to undergo a second biopsy. Furthermore, the authors were not able to account for alcohol use between biopsies and did not have accurate data on alcohol use in those with HCV alone. Although Sterling et al. did not associate any particular anti-HIV therapy with fibrosis, the specific regimen for each patient was not controlled, and the authors did not account for compliance or change in anti-HIV therapies between biopsies.
The authors recommend that all co-infected patients be repeatedly assessed for disease severity by liver biopsy analyses at periodic intervals. Because a significant proportion of patients with HIV and HCV did not have increasing liver damage, decisions on whether to begin HCV therapy should depend on patient compliance and likelihood of response, rather than concerns about rapid disease progression. Sterling et al. conclude that it is reasonable to defer HCV therapy in patients with mild disease until better therapies for HCV are available.
Changes in fibrosis about patients co-infected with HIV
and HCV and those infected with only HCV.
Read the article online:
Sterling RK, Wegelin JA, Smith PG. Similar progression of fibrosis between HIV/HCV–infected and HCV–infected patients: analysis of paired liver biopsy samples. Clin Gastroenterol and Hepatol 2010;8:1070–1076.
Read a related review:
Price JC, Thio CL. Liver disease in the HIV-infected individual. Clin Gastroenterol and Hepatol 2010;8:1002–1012.
Read the complementary Gastroenterology article:
de Vries–Slujis TEMS, Reijnders JGP, Hansen BE, et al. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus. Gastroenterology 2010;139:1934–1941.
Source
Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir †
Hepatology
Early View (Articles online in advance of print)
Fumitaka Suzuki1,*,‡, Yoshiyuki Suzuki1, Norio Akuta1, Hitomi Sezaki1, Miharu Hirakawa1, Yusuke Kawamura1, Tetsuya Hosaka1, Masahiro Kobayashi1, Satoshi Saito1, Yasuji Arase1, Kenji Ikeda1, Mariko Kobayashi2, Kazuaki Chayama3, Naoyuki Kamatani4, Yusuke Nakamura5, Yuzo Miyakawa6, Hiromitsu Kumada1
Article first published online: 18 JAN 2011
DOI: 10.1002/hep.24058
Copyright © 2011 American Association for the Study of Liver Diseases
Abstract
Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (−1.63 ± 0.92 vs. −0.48 ± 0.75 g/dL, P = 0.001) and week 4 (−3.5 ± 1.1 vs. −2.2 ± 0.96, P = 0.001), as well as at the end of treatment (−2.9 ± 1.1 vs. −2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724). Conclusion:ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes. (Hepatology 2011)
Source
Also See: Evaluating patients for genetic variations impacts adherence to antiviral therapy
Early View (Articles online in advance of print)
Fumitaka Suzuki1,*,‡, Yoshiyuki Suzuki1, Norio Akuta1, Hitomi Sezaki1, Miharu Hirakawa1, Yusuke Kawamura1, Tetsuya Hosaka1, Masahiro Kobayashi1, Satoshi Saito1, Yasuji Arase1, Kenji Ikeda1, Mariko Kobayashi2, Kazuaki Chayama3, Naoyuki Kamatani4, Yusuke Nakamura5, Yuzo Miyakawa6, Hiromitsu Kumada1
Article first published online: 18 JAN 2011
DOI: 10.1002/hep.24058
Copyright © 2011 American Association for the Study of Liver Diseases
Abstract
Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (−1.63 ± 0.92 vs. −0.48 ± 0.75 g/dL, P = 0.001) and week 4 (−3.5 ± 1.1 vs. −2.2 ± 0.96, P = 0.001), as well as at the end of treatment (−2.9 ± 1.1 vs. −2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724). Conclusion:ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes. (Hepatology 2011)
Source
Also See: Evaluating patients for genetic variations impacts adherence to antiviral therapy
P66 SVR with telaprevir, peginterferon alfa-2A and ribavirin in HCV patients with well-characterised prior null response, partial response, viral breakthrough or relapse after peginterferon+ ribavirin
Gut 2010;59:A37-A38 doi:10.1136/gut.2010.223362.92
G Dusheiko 1, T Berg 2, J M Pawlotsky 3, P Ferenci 4, S Zeuzem 5, A J Muir 6, F Poordad 7, M L Shiffman 8, J Heathcote 9, H Reesink 10, N Adda 11, J G McHutchison 6
Abstract
Introduction Study107 is an open-label rollover study of telaprevir (T) with peginterferon+ ribavirin (PR) in genotype-1 HCV patients who did not achieve SVR following PR treatment in telaprevir Phase 2 studies.
Method Null responders (<1-log10 HCV RNA decrease at week-4 or <2-log10 at week-12), partial responders (=2-log10 decrease at week 12, detectable at week 24), patients with viral breakthrough and relapsers from PROVE1/2/3 PR arms were eligible for treatment. Initially all patients received T 750 mg q8h plus PR at standard doses for 12 weeks, followed by 12 weeks of PR (T12/PR24). Protocol was amended to allow partial responders, viral breakthroughs and relapsers with undetectable HCV RNA at weeks 4 and 12 (eRVR) to receive T12/PR24. Partial responders, viral breakthroughs and relapsers with detectable HCV RNA at week 4 and/or week 12 and null responders received an additional 24 weeks of PR (T12/PR48).
Results Of 117 patients included in an ITT analysis, 97 (83%) had baseline HCV RNA=800 000 IU/ml, (69) 59% had genotype subtype 1a, 44 (38%) had cirrhosis or bridging fibrosis, and 9 (8%) were black. Viral breakthrough and relapse rates occurred in 25%, 23% of prior null responders; 10%, 22% of prior partial responders; 13%, 0% of prior viral breakthroughs; and 0%, 4% of prior relapsers.
Conclusion Patients with prior relapse, breakthrough and partial response exhibited high SVR rates after 24 weeks of telaprevir-based regimen. High SVR rates were also observed in patients with previous null response after 48 weeks of therapy.
Source
G Dusheiko 1, T Berg 2, J M Pawlotsky 3, P Ferenci 4, S Zeuzem 5, A J Muir 6, F Poordad 7, M L Shiffman 8, J Heathcote 9, H Reesink 10, N Adda 11, J G McHutchison 6
Abstract
Introduction Study107 is an open-label rollover study of telaprevir (T) with peginterferon+ ribavirin (PR) in genotype-1 HCV patients who did not achieve SVR following PR treatment in telaprevir Phase 2 studies.
Method Null responders (<1-log10 HCV RNA decrease at week-4 or <2-log10 at week-12), partial responders (=2-log10 decrease at week 12, detectable at week 24), patients with viral breakthrough and relapsers from PROVE1/2/3 PR arms were eligible for treatment. Initially all patients received T 750 mg q8h plus PR at standard doses for 12 weeks, followed by 12 weeks of PR (T12/PR24). Protocol was amended to allow partial responders, viral breakthroughs and relapsers with undetectable HCV RNA at weeks 4 and 12 (eRVR) to receive T12/PR24. Partial responders, viral breakthroughs and relapsers with detectable HCV RNA at week 4 and/or week 12 and null responders received an additional 24 weeks of PR (T12/PR48).
Results Of 117 patients included in an ITT analysis, 97 (83%) had baseline HCV RNA=800 000 IU/ml, (69) 59% had genotype subtype 1a, 44 (38%) had cirrhosis or bridging fibrosis, and 9 (8%) were black. Viral breakthrough and relapse rates occurred in 25%, 23% of prior null responders; 10%, 22% of prior partial responders; 13%, 0% of prior viral breakthroughs; and 0%, 4% of prior relapsers.
Conclusion Patients with prior relapse, breakthrough and partial response exhibited high SVR rates after 24 weeks of telaprevir-based regimen. High SVR rates were also observed in patients with previous null response after 48 weeks of therapy.
Source
Trends in all cause and liver-related hospitalizations in people with hepatitis B or C: a population-based linkage study
Published on: 2011-01-25
Previous studies have reported an excess burden of cancer and mortality in populations with chronic hepatitis B (HBV) or C (HCV), but there are limited data comparing hospitalization rates. In this study, we compared hospitalization rates for all causes and viral liver disease in people notified with HBV or HCV in New South Wales (NSW), Australia.
Methods: HBV and HCV notifications were linked to their hospital (July 2000-June 2006), HIV and death records.
Standardized hospitalization ratios (SHRs) were calculated using rates for the NSW population. Random effects Poisson regression was used to examine temporal trends.
Results: The SHR for all causes and non alcoholic liver disease was two-fold higher in the HCV cohort compared with the HBV cohort (SHRs 1.4 (95%CI: 1.4-1.4) v 0.6 (95%CI: 0.6-0.6) and 14.0 (95%CI: 12.7-15.4) v 5.4 (95%CI: 4.5-6.4), respectively), whilst the opposite was seen for primary liver cancer (SHRs 16.2 (95%CI: 13.8-19.1) v 29.1 (95%CI: 24.7-34.2)).
HIV co-infection doubled the SHR except for primary liver cancer in the HCV/HIV cohort. In HBV and HCV mono-infected cohorts, all cause hospitalization rates declined and primary liver cancer rates increased, whilst rates for non alcoholic liver disease increased by 9% in the HCV cohort but decreased by 14% in the HBV cohort (P <0.001).
Conclusion: Hospital-related morbidity overall and for non alcoholic liver disease was considerably higher for HCV than HBV.
Improved treatment of advanced HBV-related liver disease may explain why HBV liver-related morbidity declined. In contrast, HCV liver-related morbidity increased and improved treatments, especially for advanced liver disease, and higher levels of treatment uptake are required to reverse this trend.
Author: Heather GiddingGregory DoreJanaki AminMatthew Law
Credits/Source: BMC Public Health 2011, 11:52
Source
Previous studies have reported an excess burden of cancer and mortality in populations with chronic hepatitis B (HBV) or C (HCV), but there are limited data comparing hospitalization rates. In this study, we compared hospitalization rates for all causes and viral liver disease in people notified with HBV or HCV in New South Wales (NSW), Australia.
Methods: HBV and HCV notifications were linked to their hospital (July 2000-June 2006), HIV and death records.
Standardized hospitalization ratios (SHRs) were calculated using rates for the NSW population. Random effects Poisson regression was used to examine temporal trends.
Results: The SHR for all causes and non alcoholic liver disease was two-fold higher in the HCV cohort compared with the HBV cohort (SHRs 1.4 (95%CI: 1.4-1.4) v 0.6 (95%CI: 0.6-0.6) and 14.0 (95%CI: 12.7-15.4) v 5.4 (95%CI: 4.5-6.4), respectively), whilst the opposite was seen for primary liver cancer (SHRs 16.2 (95%CI: 13.8-19.1) v 29.1 (95%CI: 24.7-34.2)).
HIV co-infection doubled the SHR except for primary liver cancer in the HCV/HIV cohort. In HBV and HCV mono-infected cohorts, all cause hospitalization rates declined and primary liver cancer rates increased, whilst rates for non alcoholic liver disease increased by 9% in the HCV cohort but decreased by 14% in the HBV cohort (P <0.001).
Conclusion: Hospital-related morbidity overall and for non alcoholic liver disease was considerably higher for HCV than HBV.
Improved treatment of advanced HBV-related liver disease may explain why HBV liver-related morbidity declined. In contrast, HCV liver-related morbidity increased and improved treatments, especially for advanced liver disease, and higher levels of treatment uptake are required to reverse this trend.
Author: Heather GiddingGregory DoreJanaki AminMatthew Law
Credits/Source: BMC Public Health 2011, 11:52
Source
How ZymoGenetics Coulda Been a Contender: The Big Break That Came Too Late
Luke Timmerman 1/25/11
ZymoGenetics, if it had stayed an independent company in Seattle, would be worth tens of millions of dollars more today than what it was in September when it agreed to be acquired by Bristol-Myers Squibb (NYSE: BMY).
Bristol clearly scored a big break with its new ZymoGenetics assets on December 21, about two months after it closed the books on its $885 million acquisition of the venerable Seattle biotech.
If it had still been an independent biotech, the value of ZymoGenetics would have soared that day when Cambridge, MA-based Vertex Pharmaceuticals announced that, essentially, it had failed to make ZymoGenetics’ lead drug candidate obsolete. On that day, Vertex (NASDAQ: VRTX) said it was unable to eradicate one of backbone components of hepatitis C therapy in a high profile clinical trial.
Vertex is blazing a new trail in the field with a potent new oral pill that generates unprecedented cure rates when given in combination with two standard treatments—pegylated interferon alpha and ribavirin. Vertex was hoping to raise the bar even higher, to find out if its lead molecule, telaprevir, could be combined into a new cocktail regimen that Vertex hoped would kick old-school interferon into the dustbin of history. Doctors and patients have been yearning for a way to get rid of interferon, which causes nasty flu-like symptoms that make patients feel awful for months, which discourages most patients from seeking treatment today.
ZymoGenetics, knowing this well, had developed a genetically modified version of interferon, which it called pegylated interferon lambda. This new form of interferon was designed to kill the hepatitis C virus just like the older version of interferon, but without the flu-like side effects. Results from early clinical trials were so promising that ZymoGenetics was able to entice Bristol to sign a $1.1 billion partnership to co-develop the drug in January 2009.
But many on Wall Street weren’t impressed. They had fallen head over heels for Vertex’s new molecule, insisting that ZymoGenetics and Bristol were wasting their time with a new type of interferon. Vertex, they said, was coming along with a cocktail approach of new oral pills that would get rid of interferon, meaning any improvement on old-school interferon would soon be irrelevant. While many doctors, and companies like Vertex still hope it will be possible to do this, the latest clinical trial failure makes it clear that interferon will be part of the standard treatment regimen for years. That means the drug Bristol acquired from ZymoGenetics has a chance to integrate itself into a new standard of care, at a moment when awareness has never been higher among an estimated 6 million U.S. and European patients with this liver-damaging condition.
Former ZymoGenetics CEO Doug Williams, who recently took a new job as head of R&D at Weston, MA-based Biogen Idec, acknowledged in a recent interview that the failure of Vertex’s combination trial would have been a positive turn of events for ZymoGenetics and its pegylated interferon lambda program. He stopped short of saying that Wall Street would have perceived the development in a way that would have boosted ZymoGenetics’ stock price.
“Certainly some will people would have come off the fence and perhaps started to believe that interferons will be really hard to get rid of,” Williams says. “I’m certainly of the mind that it will be extremely difficult to get rid of interferon, and achieve [cure rates] currently seen.”
He added: “I gotta believe it would have been viewed as a net positive, but the degree to which it would have been reflected in the stock price, I don’t think anybody can say that.”
David Miller, the president of Biotech Stock Research in Seattle, who criticized ZymoGenetics for selling the company at a bargain price, said he believes investors would have given the company credit. An estimated 6 million patients in the U.S. and Europe have hepatitis C, and many of them are expected to start seeking treatment in 2011, now that a new wave of protease inhibitors like Vertex’s telaprevir and Merck’s boceprevir are being primed to hit the market later this year. The existing interferons from Roche and Merck made up a combined market worth more than $2 billion in 2009, even before the more-effective protease inhibitors came along to spur more interest in hepatitis C therapy.
ZymoGenetics could have seen its stock climb another $2 to $3 a share if it had still been an independent company when the Vertex news hit the wire on December 21, Miller says.
“Smart money was moving toward ZymoGenetics,” Miller says. The latest clinical trial failure of the no-interferon regimen, Miller says, “would have been huge for ZymoGenetics. People were starting to understand that interferons aren’t going anyway anytime soon. This press release (from Vertex) would have cemented that.”
Now that doctors are getting accustomed to seeing hepatitis C cure rates in the neighborhood of 70 to 75 percent of patients who take the combo regimen of the Vertex drug, plus interferon and ribavirin, it’s unlikely they will ever sacrifice even a few percentage points of effectiveness just to get rid of interferon’s side effects, Williams says. That means the bar is high for any oral pill cocktail regimen that aspires to get rid of interferon. It’s certainly possible that the combination of doses, and schedules, could coalesce to make that happen, but it will take years to figure out in clinical trials, Williams says.
Given that was what ZymoGenetics management was betting on with their new interferon, and that its thesis was essentially validated on December 21st, I had to ask Williams if he regrets selling the company for less than a billion dollars. He said no.
“I don’t look back on these sorts of decisions,” Williams says. “You make the decision you have to make at the time with the information you have available to you at the time. I feel we made the right decision at the right time.”
Source
ZymoGenetics, if it had stayed an independent company in Seattle, would be worth tens of millions of dollars more today than what it was in September when it agreed to be acquired by Bristol-Myers Squibb (NYSE: BMY).
Bristol clearly scored a big break with its new ZymoGenetics assets on December 21, about two months after it closed the books on its $885 million acquisition of the venerable Seattle biotech.
If it had still been an independent biotech, the value of ZymoGenetics would have soared that day when Cambridge, MA-based Vertex Pharmaceuticals announced that, essentially, it had failed to make ZymoGenetics’ lead drug candidate obsolete. On that day, Vertex (NASDAQ: VRTX) said it was unable to eradicate one of backbone components of hepatitis C therapy in a high profile clinical trial.
Vertex is blazing a new trail in the field with a potent new oral pill that generates unprecedented cure rates when given in combination with two standard treatments—pegylated interferon alpha and ribavirin. Vertex was hoping to raise the bar even higher, to find out if its lead molecule, telaprevir, could be combined into a new cocktail regimen that Vertex hoped would kick old-school interferon into the dustbin of history. Doctors and patients have been yearning for a way to get rid of interferon, which causes nasty flu-like symptoms that make patients feel awful for months, which discourages most patients from seeking treatment today.
ZymoGenetics, knowing this well, had developed a genetically modified version of interferon, which it called pegylated interferon lambda. This new form of interferon was designed to kill the hepatitis C virus just like the older version of interferon, but without the flu-like side effects. Results from early clinical trials were so promising that ZymoGenetics was able to entice Bristol to sign a $1.1 billion partnership to co-develop the drug in January 2009.
But many on Wall Street weren’t impressed. They had fallen head over heels for Vertex’s new molecule, insisting that ZymoGenetics and Bristol were wasting their time with a new type of interferon. Vertex, they said, was coming along with a cocktail approach of new oral pills that would get rid of interferon, meaning any improvement on old-school interferon would soon be irrelevant. While many doctors, and companies like Vertex still hope it will be possible to do this, the latest clinical trial failure makes it clear that interferon will be part of the standard treatment regimen for years. That means the drug Bristol acquired from ZymoGenetics has a chance to integrate itself into a new standard of care, at a moment when awareness has never been higher among an estimated 6 million U.S. and European patients with this liver-damaging condition.
Former ZymoGenetics CEO Doug Williams, who recently took a new job as head of R&D at Weston, MA-based Biogen Idec, acknowledged in a recent interview that the failure of Vertex’s combination trial would have been a positive turn of events for ZymoGenetics and its pegylated interferon lambda program. He stopped short of saying that Wall Street would have perceived the development in a way that would have boosted ZymoGenetics’ stock price.
“Certainly some will people would have come off the fence and perhaps started to believe that interferons will be really hard to get rid of,” Williams says. “I’m certainly of the mind that it will be extremely difficult to get rid of interferon, and achieve [cure rates] currently seen.”
He added: “I gotta believe it would have been viewed as a net positive, but the degree to which it would have been reflected in the stock price, I don’t think anybody can say that.”
David Miller, the president of Biotech Stock Research in Seattle, who criticized ZymoGenetics for selling the company at a bargain price, said he believes investors would have given the company credit. An estimated 6 million patients in the U.S. and Europe have hepatitis C, and many of them are expected to start seeking treatment in 2011, now that a new wave of protease inhibitors like Vertex’s telaprevir and Merck’s boceprevir are being primed to hit the market later this year. The existing interferons from Roche and Merck made up a combined market worth more than $2 billion in 2009, even before the more-effective protease inhibitors came along to spur more interest in hepatitis C therapy.
ZymoGenetics could have seen its stock climb another $2 to $3 a share if it had still been an independent company when the Vertex news hit the wire on December 21, Miller says.
“Smart money was moving toward ZymoGenetics,” Miller says. The latest clinical trial failure of the no-interferon regimen, Miller says, “would have been huge for ZymoGenetics. People were starting to understand that interferons aren’t going anyway anytime soon. This press release (from Vertex) would have cemented that.”
Now that doctors are getting accustomed to seeing hepatitis C cure rates in the neighborhood of 70 to 75 percent of patients who take the combo regimen of the Vertex drug, plus interferon and ribavirin, it’s unlikely they will ever sacrifice even a few percentage points of effectiveness just to get rid of interferon’s side effects, Williams says. That means the bar is high for any oral pill cocktail regimen that aspires to get rid of interferon. It’s certainly possible that the combination of doses, and schedules, could coalesce to make that happen, but it will take years to figure out in clinical trials, Williams says.
Given that was what ZymoGenetics management was betting on with their new interferon, and that its thesis was essentially validated on December 21st, I had to ask Williams if he regrets selling the company for less than a billion dollars. He said no.
“I don’t look back on these sorts of decisions,” Williams says. “You make the decision you have to make at the time with the information you have available to you at the time. I feel we made the right decision at the right time.”
Source
Survival following transplant surgery for liver cancer not impacted by HIV-positive status
25. January 2011 08:43
French researchers determined that infection with human immunodeficiency virus (HIV) impaired results of transplant surgery for liver cancer, with more HIV infected patients dropping off the transplantation wait list. The team found that overall survival and recurrence-free survival was not impacted following liver transplantation in patients with controlled HIV disease. Details of this single center study—the largest to date—are published in the February issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).
More than 40 million individuals are infected with HIV; of these roughly two to four million and four to five million are also carriers of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. With the introduction of highly active antiretroviral therapy (HAART) in 1996 the survival of patients with HIV infection has improved dramatically and now end-stage liver disease has become the principal cause of death among HIV- positive patients co-infected HBV or HCV. Prior studies have shown that 25% of liver-related mortality in HIV-positive patients is attributable to hepatocellular carcinoma (HCC), or liver cancer.
"Liver transplantation is the optimum treatment for HCC and can also be considered for controlled HIV-positive patients with liver cancer," said René Adam, MD, PhD, from Hospital Paul Brousse in France and lead author of the current study. "Our study showed that HIV infection impaired the results of liver transplantation on an intent-to-treat basis but exerted no significant impact on overall survival and recurrence-free survival following transplantation."
The research team analyzed data from 21 HIV-infected and 65 HIV-negative patients with HCC who were listed for liver transplantation between 2003 and 2008. All HIV-positive patients were treated with HAART and had not experience any AIDS event or opportunistic infections prior to being place on the wait list.
Researchers observed a trend towards a higher drop-out among HIV-positive wait listed patients (23%) compared to patients without HIV (10%). Patients with HIV who dropped out had significantly higher alpha-fetoprotein (AFP) levels at the time of listing than those who received a transplant—98 μg/L versus 12 μg/L, respectively. A similar difference in AFP levels was not found in HIV-negative patients—18 μg/L in those who dropped out versus 13 μg/L for those who underwent liver transplantation. Only one HIV-positive patient who did not have increased AFP levels while on the wait list dropped out due to progression from controlled HIV to AIDS.
Medical evidence indicates a major predictive factor for HCC recurrence post-transplantation is an increase in patient's AFP level of more than 15 μg/L per month while on the waiting list. "Our study confirmed the importance of this preoperative factor (AFP levels), as all HIV-positive patients who dropped out displayed a rise in AFP levels," Dr. Adam concluded. "There is clearly a critical need for more effective neoadjuvant therapy in HIV-positive patients with HCC, however there are no objective arguments to contraindicate liver transplantation in this group if strict criteria are used for selection and patients are closely monitored until surgery."
Source Hepatology
Source
French researchers determined that infection with human immunodeficiency virus (HIV) impaired results of transplant surgery for liver cancer, with more HIV infected patients dropping off the transplantation wait list. The team found that overall survival and recurrence-free survival was not impacted following liver transplantation in patients with controlled HIV disease. Details of this single center study—the largest to date—are published in the February issue of Hepatology, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).
More than 40 million individuals are infected with HIV; of these roughly two to four million and four to five million are also carriers of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), respectively. With the introduction of highly active antiretroviral therapy (HAART) in 1996 the survival of patients with HIV infection has improved dramatically and now end-stage liver disease has become the principal cause of death among HIV- positive patients co-infected HBV or HCV. Prior studies have shown that 25% of liver-related mortality in HIV-positive patients is attributable to hepatocellular carcinoma (HCC), or liver cancer.
"Liver transplantation is the optimum treatment for HCC and can also be considered for controlled HIV-positive patients with liver cancer," said René Adam, MD, PhD, from Hospital Paul Brousse in France and lead author of the current study. "Our study showed that HIV infection impaired the results of liver transplantation on an intent-to-treat basis but exerted no significant impact on overall survival and recurrence-free survival following transplantation."
The research team analyzed data from 21 HIV-infected and 65 HIV-negative patients with HCC who were listed for liver transplantation between 2003 and 2008. All HIV-positive patients were treated with HAART and had not experience any AIDS event or opportunistic infections prior to being place on the wait list.
Researchers observed a trend towards a higher drop-out among HIV-positive wait listed patients (23%) compared to patients without HIV (10%). Patients with HIV who dropped out had significantly higher alpha-fetoprotein (AFP) levels at the time of listing than those who received a transplant—98 μg/L versus 12 μg/L, respectively. A similar difference in AFP levels was not found in HIV-negative patients—18 μg/L in those who dropped out versus 13 μg/L for those who underwent liver transplantation. Only one HIV-positive patient who did not have increased AFP levels while on the wait list dropped out due to progression from controlled HIV to AIDS.
Medical evidence indicates a major predictive factor for HCC recurrence post-transplantation is an increase in patient's AFP level of more than 15 μg/L per month while on the waiting list. "Our study confirmed the importance of this preoperative factor (AFP levels), as all HIV-positive patients who dropped out displayed a rise in AFP levels," Dr. Adam concluded. "There is clearly a critical need for more effective neoadjuvant therapy in HIV-positive patients with HCC, however there are no objective arguments to contraindicate liver transplantation in this group if strict criteria are used for selection and patients are closely monitored until surgery."
Source Hepatology
Source
Evaluating patients for genetic variations impacts adherence to antiviral therapy
25. January 2011 08:39
In two recent studies, researchers have identified two functional variants in the inosine triphosphatase (ITPA) gene that protect patients with hepatitis C virus (HCV) against anemia brought on by antiviral treatment. The ability to identify those patients protected against treatment-induced anemia will ensure completion of antiviral therapy and successful elimination of the virus. Full findings of these studies appear in the February issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.
Chronic HCV affects up to 170 million individuals worldwide and is a leading cause of end-stage liver disease. While HCV is curable with treatment of pegylated interferon (pegIFN) and ribavirin (RBV), many patients have difficulty tolerating these antiviral drugs. Prior studies have shown that 9% to 22% of patients enrolled in phase III trials of pegIFN plus RBV require modification of their dose due to hemolytic anemia brought on by the drugs. A reduction in RBV limits treatment efficacy, thus impacting the viral clearance success rate.
Alessandra Mangia, M.D., from Casa Sollievo della Sofferenza Hospital in Italy, and colleagues evaluated the association between ITPA variants and anemia in a cohort of 238 Caucasian patients treated with variable pegIFN and weight-based doses of RBV. The research team found that the ITPA variants were strongly and independently associated with protection from anemia, but did not provide an increase in sustained virological response.
"When anemia develops only four weeks after the start of treatment, physicians are required to immediately reduce ribavirin dosages. This early reduction will affect the overall duration of treatment which, with the combination of pegIFN and RBV, lasts 24 weeks for patients infected with HCV genotypes two and 3 (G2/3) and 48 weeks for patients with HCV genotype one (G1) infection. Currently, only the use of the drug erythropoietin (EPO)—an expensive drug that due to its high cost cannot be reimbursed in several countries—might prevent unsuccessful antiviral treatment in these cases," explained Dr. Mangia.
"Our findings demonstrated that ITPA variants are strongly associated with protection from week four anemia and help us in selecting in advance who will need early ribavirin dose reduction and possibly supportive EPO treatment. This may lead to a more rational use of economical resources and to an individualized use of supportive EPO treatment," concluded Dr. Mangia. "Patients with a genetic profile that included the two ITPA variants may be safely administered higher doses of RBV, increasing the likelihood of HCV elimination after treatment—an important finding given that to achieve viral clearance high dosages of RBV need to be used in the early phases of treatment."
A related study led by Fumitaka Suzuki, M.D., from Toranomon Hospital in Japan found similar results in its cohort of 61 Japanese patients with HCV. Patients in this study received a triple therapy of pegINF, RBV and the protease inhibitor, telaprevir. Dr. Suzuki and colleagues found that ITPA variants impacted blood levels; however a sustained virological response could be achieved with careful monitoring of anemia and prompt adjustment of RBV dose. The authors suggest that future investigation of the influence of ITPA gene variants on RBV-induced anemia are needed on larger scales and on patients of various ethnicities.
SOURCE Hepatology
Source
In two recent studies, researchers have identified two functional variants in the inosine triphosphatase (ITPA) gene that protect patients with hepatitis C virus (HCV) against anemia brought on by antiviral treatment. The ability to identify those patients protected against treatment-induced anemia will ensure completion of antiviral therapy and successful elimination of the virus. Full findings of these studies appear in the February issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.
Chronic HCV affects up to 170 million individuals worldwide and is a leading cause of end-stage liver disease. While HCV is curable with treatment of pegylated interferon (pegIFN) and ribavirin (RBV), many patients have difficulty tolerating these antiviral drugs. Prior studies have shown that 9% to 22% of patients enrolled in phase III trials of pegIFN plus RBV require modification of their dose due to hemolytic anemia brought on by the drugs. A reduction in RBV limits treatment efficacy, thus impacting the viral clearance success rate.
Alessandra Mangia, M.D., from Casa Sollievo della Sofferenza Hospital in Italy, and colleagues evaluated the association between ITPA variants and anemia in a cohort of 238 Caucasian patients treated with variable pegIFN and weight-based doses of RBV. The research team found that the ITPA variants were strongly and independently associated with protection from anemia, but did not provide an increase in sustained virological response.
"When anemia develops only four weeks after the start of treatment, physicians are required to immediately reduce ribavirin dosages. This early reduction will affect the overall duration of treatment which, with the combination of pegIFN and RBV, lasts 24 weeks for patients infected with HCV genotypes two and 3 (G2/3) and 48 weeks for patients with HCV genotype one (G1) infection. Currently, only the use of the drug erythropoietin (EPO)—an expensive drug that due to its high cost cannot be reimbursed in several countries—might prevent unsuccessful antiviral treatment in these cases," explained Dr. Mangia.
"Our findings demonstrated that ITPA variants are strongly associated with protection from week four anemia and help us in selecting in advance who will need early ribavirin dose reduction and possibly supportive EPO treatment. This may lead to a more rational use of economical resources and to an individualized use of supportive EPO treatment," concluded Dr. Mangia. "Patients with a genetic profile that included the two ITPA variants may be safely administered higher doses of RBV, increasing the likelihood of HCV elimination after treatment—an important finding given that to achieve viral clearance high dosages of RBV need to be used in the early phases of treatment."
A related study led by Fumitaka Suzuki, M.D., from Toranomon Hospital in Japan found similar results in its cohort of 61 Japanese patients with HCV. Patients in this study received a triple therapy of pegINF, RBV and the protease inhibitor, telaprevir. Dr. Suzuki and colleagues found that ITPA variants impacted blood levels; however a sustained virological response could be achieved with careful monitoring of anemia and prompt adjustment of RBV dose. The authors suggest that future investigation of the influence of ITPA gene variants on RBV-induced anemia are needed on larger scales and on patients of various ethnicities.
SOURCE Hepatology
Source
January 24, 2011
Check-up liver biopsy
The Irish Times - Tuesday, January 25, 2011
MARION KERR
I’m booked in for a liver biopsy and wonder what the procedure will involve?
A liver biopsy is used to help diagnose many liver diseases. The procedure can help assess the stage of liver disease in conditions such as hepatitis C infection. It may also detect cancer, infections and the cause of abnormal levels of liver enzymes found in blood tests.
A liver biopsy takes a sample of tissue from the liver for laboratory examination. It may be performed either as a day-case procedure or during a hospital admission.
A sedative medication or pain medication is usually given by injection before the test. If the biopsy is done through the abdominal wall, you will be lying on your back with your right hand under your head. You will be asked to lie as still as possible throughout the test.
Ultrasound is used to guide the biopsy needle. The skin is cleansed, and local anaesthetic injected to numb the area. A small cut is made in the skin.
The biopsy needle is inserted, usually guided by ultrasound. You will be instructed to hold your breath while the biopsy is taken. This is to reduce the chance of puncturing the lung or tearing the liver.
Once the biopsy needle is removed, pressure will be applied to stop the bleeding and a bandage placed over the insertion site.
My doctor said something about having the test done through a vein in my neck.
Liver biopsy can also be performed by inserting a needle into the jugular vein in the neck. Again, you will lie on your back on a table and the internal jugular vein will be located. The skin will be cleansed and local anaesthetic will be injected to numb the area. A needle is then inserted to pass a catheter through the veins to the liver. X-ray equipment will be used to check the location of the catheter.
A specialised needle is then used through the catheter to take the biopsy sample. In both types of biopsy, you may feel a mild stinging sensation from the anaesthetic needle and when the anaesthetic is injected. The biopsy needle may feel like deep pressure and dull pain. Some people experience pain in the shoulder.
Risks may include a collapsed lung, complications from the sedation, accidental injury to the gallbladder or kidney and internal bleeding.
Source
MARION KERR
I’m booked in for a liver biopsy and wonder what the procedure will involve?
A liver biopsy is used to help diagnose many liver diseases. The procedure can help assess the stage of liver disease in conditions such as hepatitis C infection. It may also detect cancer, infections and the cause of abnormal levels of liver enzymes found in blood tests.
A liver biopsy takes a sample of tissue from the liver for laboratory examination. It may be performed either as a day-case procedure or during a hospital admission.
A sedative medication or pain medication is usually given by injection before the test. If the biopsy is done through the abdominal wall, you will be lying on your back with your right hand under your head. You will be asked to lie as still as possible throughout the test.
Ultrasound is used to guide the biopsy needle. The skin is cleansed, and local anaesthetic injected to numb the area. A small cut is made in the skin.
The biopsy needle is inserted, usually guided by ultrasound. You will be instructed to hold your breath while the biopsy is taken. This is to reduce the chance of puncturing the lung or tearing the liver.
Once the biopsy needle is removed, pressure will be applied to stop the bleeding and a bandage placed over the insertion site.
My doctor said something about having the test done through a vein in my neck.
Liver biopsy can also be performed by inserting a needle into the jugular vein in the neck. Again, you will lie on your back on a table and the internal jugular vein will be located. The skin will be cleansed and local anaesthetic will be injected to numb the area. A needle is then inserted to pass a catheter through the veins to the liver. X-ray equipment will be used to check the location of the catheter.
A specialised needle is then used through the catheter to take the biopsy sample. In both types of biopsy, you may feel a mild stinging sensation from the anaesthetic needle and when the anaesthetic is injected. The biopsy needle may feel like deep pressure and dull pain. Some people experience pain in the shoulder.
Risks may include a collapsed lung, complications from the sedation, accidental injury to the gallbladder or kidney and internal bleeding.
Source
Outcome of liver transplantation based on donor graft quality and recipient status
Transplant Proc. 2010 Jul-Aug;42(6):2327-30.
Nemes B, Gelley F, Zádori G, Piros L, Perneczky J, Kóbori L, Fehérvári I, Görög D.
Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary. nemes@trans.sote.hu
Abstract
BACKGROUND: Availability of suitable donor organs has always limited the number of liver transplantations performed. Use of marginal donor organs is an alternative to overcome organ shortage.
OBJECTIVE: To analyze the effect of various combinations of donor organ quality and recipient status on the outcome of liver transplantation.
MATERIALS AND METHODS: Data from 260 whole-liver transplantations performed between January 2003 and September 2009 were analyzed retrospectively. Study groups were established according to donor organ quality (marginal score 0-1 vs 2-5) and recipient status (Model for End-Stage Liver Disease [MELD] score <17 or >17). In patients at low risk, 102 received optimal grafts (good-to-good group [G/G], and 75 received marginal grafts (bad-to-good group [B/G]. In patients at high risk, 46 received optimal grafts (good-to-bad group [G/B], and 37 received marginal grafts (bad-to-bad group [B/B].
RESULTS: No differences were observed in cumulative patient and graft survival rates; however, total survival differed in the early period after transplantation, that is, within 1 year. There was a higher rate of overall postoperative complications including initial poor graft function, bleeding, infection, and kidney failure in group B/B compared with group G/B (25 of 37 patients [67.5%] vs 27 of 46 patients [59.0%]), group B/G (25 of 37 patients [68%] vs 39 of 75 patients [52%], and group G/G (25 of 37 patients [68%] vs 43 of 102 patients [42%]) (P = .04). Patients with a high MELD score (G/B and B/B) demonstrated increased risk of postoperative complications. Use of donor organs with marginal score of 2 or higher in patients with high MELD scores increased early patient mortality.
CONCLUSION: In summary, patients with a high MELD score (G/B and B/B) are at an increased risk of post-OLT complications. In contrast, use of marginal grafts (B/G and B/B) increased the rate of hepatitis C virus recurrence and decreased the response rate to antiviral therapy. The combination of impaired donor grafts and recipients at high risk should be avoided.
Copyright 2010 Elsevier Inc. All rights reserved.
PMID: 20692473 [PubMed - indexed for MEDLINE]
Source
Nemes B, Gelley F, Zádori G, Piros L, Perneczky J, Kóbori L, Fehérvári I, Görög D.
Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary. nemes@trans.sote.hu
Abstract
BACKGROUND: Availability of suitable donor organs has always limited the number of liver transplantations performed. Use of marginal donor organs is an alternative to overcome organ shortage.
OBJECTIVE: To analyze the effect of various combinations of donor organ quality and recipient status on the outcome of liver transplantation.
MATERIALS AND METHODS: Data from 260 whole-liver transplantations performed between January 2003 and September 2009 were analyzed retrospectively. Study groups were established according to donor organ quality (marginal score 0-1 vs 2-5) and recipient status (Model for End-Stage Liver Disease [MELD] score <17 or >17). In patients at low risk, 102 received optimal grafts (good-to-good group [G/G], and 75 received marginal grafts (bad-to-good group [B/G]. In patients at high risk, 46 received optimal grafts (good-to-bad group [G/B], and 37 received marginal grafts (bad-to-bad group [B/B].
RESULTS: No differences were observed in cumulative patient and graft survival rates; however, total survival differed in the early period after transplantation, that is, within 1 year. There was a higher rate of overall postoperative complications including initial poor graft function, bleeding, infection, and kidney failure in group B/B compared with group G/B (25 of 37 patients [67.5%] vs 27 of 46 patients [59.0%]), group B/G (25 of 37 patients [68%] vs 39 of 75 patients [52%], and group G/G (25 of 37 patients [68%] vs 43 of 102 patients [42%]) (P = .04). Patients with a high MELD score (G/B and B/B) demonstrated increased risk of postoperative complications. Use of donor organs with marginal score of 2 or higher in patients with high MELD scores increased early patient mortality.
CONCLUSION: In summary, patients with a high MELD score (G/B and B/B) are at an increased risk of post-OLT complications. In contrast, use of marginal grafts (B/G and B/B) increased the rate of hepatitis C virus recurrence and decreased the response rate to antiviral therapy. The combination of impaired donor grafts and recipients at high risk should be avoided.
Copyright 2010 Elsevier Inc. All rights reserved.
PMID: 20692473 [PubMed - indexed for MEDLINE]
Source
Factors predictive of sustained virological response following 72 weeks of combination therapy for genotype 1b hepatitis C
J Gastroenterol. 2011 Jan 19. [Epub ahead of print]
Chayama K, Hayes CN, Yoshioka K, Moriwaki H, Okanoue T, Sakisaka S, Takehara T, Oketani M, Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H, Seike M, Ueno Y, Yotsuyanagi H, Kumada H.
Department of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan, chayama@hiroshima-u.ac.jp.
Abstract
BACKGROUND: Treatment of genotype 1b chronic hepatitis C virus (HCV) infection has been improved by extending peg-interferon plus ribavirin combination therapy to 72 weeks, but predictive factors are needed to identify those patients who are likely to respond to long-term therapy.
METHODS: We analyzed amino acid (aa) substitutions in the core protein and the interferon sensitivity determining region (ISDR) of nonstructural protein (NS) 5A in 840 genotype 1b chronic hepatitis C patients with high viral load. We used logistic regression and classification and regression tree (CART) analysis to identify predictive factors for sustained virological response (SVR) for patients undergoing 72 weeks of treatment.
RESULTS: When patients were separately analyzed by treatment duration using multivariate logistic regression, several factors, including sex, age, viral load, and core aa70 and ISDR substitutions (P = 0.0003, P = 0.02, P = 0.01, P = 0.0001, and P = 0.0004, respectively) were significant predictive factors for SVR with 48 weeks of treatment, whereas age, previous interferon treatment history, and ISDR substitutions (P = 0.03, P = 0.01, and P = 0.02, respectively) were the only significant predictive factors with 72 weeks of treatment. Using CART analysis, a decision tree was generated that identified age, cholesterol, sex, treatment length, and aa70 and ISDR substitutions as the most important predictive factors. The CART model had a sensitivity of 69.2% and specificity of 60%, with a positive predictive value of 68.4%.
CONCLUSIONS: Complementary statistical and data mining approaches were used to identify a subgroup of patients likely to benefit from 72 weeks of therapy.
PMID: 21246384 [PubMed - as supplied by publisher]
Source
Chayama K, Hayes CN, Yoshioka K, Moriwaki H, Okanoue T, Sakisaka S, Takehara T, Oketani M, Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H, Seike M, Ueno Y, Yotsuyanagi H, Kumada H.
Department of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan, chayama@hiroshima-u.ac.jp.
Abstract
BACKGROUND: Treatment of genotype 1b chronic hepatitis C virus (HCV) infection has been improved by extending peg-interferon plus ribavirin combination therapy to 72 weeks, but predictive factors are needed to identify those patients who are likely to respond to long-term therapy.
METHODS: We analyzed amino acid (aa) substitutions in the core protein and the interferon sensitivity determining region (ISDR) of nonstructural protein (NS) 5A in 840 genotype 1b chronic hepatitis C patients with high viral load. We used logistic regression and classification and regression tree (CART) analysis to identify predictive factors for sustained virological response (SVR) for patients undergoing 72 weeks of treatment.
RESULTS: When patients were separately analyzed by treatment duration using multivariate logistic regression, several factors, including sex, age, viral load, and core aa70 and ISDR substitutions (P = 0.0003, P = 0.02, P = 0.01, P = 0.0001, and P = 0.0004, respectively) were significant predictive factors for SVR with 48 weeks of treatment, whereas age, previous interferon treatment history, and ISDR substitutions (P = 0.03, P = 0.01, and P = 0.02, respectively) were the only significant predictive factors with 72 weeks of treatment. Using CART analysis, a decision tree was generated that identified age, cholesterol, sex, treatment length, and aa70 and ISDR substitutions as the most important predictive factors. The CART model had a sensitivity of 69.2% and specificity of 60%, with a positive predictive value of 68.4%.
CONCLUSIONS: Complementary statistical and data mining approaches were used to identify a subgroup of patients likely to benefit from 72 weeks of therapy.
PMID: 21246384 [PubMed - as supplied by publisher]
Source
Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States
Ann Intern Med. 2011 Jan 18;154(2):85-93.
Davila JA, Henderson L, Kramer JR, Kanwal F, Richardson PA, Duan Z, El-Serag HB.
the Houston Center for Quality of Care and Utilization Studies, The Michael E. DeBakey Veterans Affairs Medical Center, and Baylor College of Medicine, Houston, Texas; University of North Carolina, Chapel Hill, North Carolina; and St. Louis University School of Medicine, St. Louis, Missouri.
Abstract
Background: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with hepatitis C virus (HCV) infection and cirrhosis. However, whether surveillance is being done as recommended is unknown. Objective: To examine the prevalence and determinants of HCC surveillance among HCV-infected patients with cirrhosis in Veterans Affairs (VA) health care facilities in the United States. Design: Retrospective cohort study of HCV-infected patients using data obtained from the national VA Hepatitis C Clinical Case Registry. Setting: 128 VA medical centers. Patients: HCV-infected patients with cirrhosis diagnosed between fiscal years 1998 and 2005. Measurements: Abdominal ultrasonography and measurement of α-fetoprotein for HCC surveillance were identified from administrative data by using a previously validated algorithm. Patients were categorized as having routine (tests done during at least 2 consecutive years in the 4 years after cirrhosis diagnosis), inconsistent (at least 1 test, but not routine), or no surveillance in the 4 years after cirrhosis diagnosis. Predictors of surveillance were identified by using hierarchical random-effects regression. Results: 126 670 patients with HCV were identified; 13 002 (10.1%) had cirrhosis. Approximately 42.0% of patients with cirrhosis received 1 or more HCC surveillance tests within the first year after the cirrhosis index date; however, a decline in receipt of surveillance was observed in the following 2 to 4 years. Among patients with cirrhosis and at least 2 years of follow-up, routine surveillance occurred in 12.0%, inconsistent surveillance in 58.5%, and no surveillance in 29.5%. Lower medical and psychological comorbid conditions, presence of varices, and the absence of decompensated liver disease were associated with a higher likelihood of receiving routine surveillance. Limitations: Hepatocellular carcinoma surveillance tests were indirectly identified from registry data. Physician recommendations could not be captured. Conclusion: Few HCV-infected veterans with cirrhosis received routine HCC surveillance. New strategies are needed to improve the implementation of HCC surveillance in clinical practice. Primary Funding Source: Houston Veterans Affairs Health Services Research and Development Center of Excellence and the National Cancer Institute.
PMID: 21242365 [PubMed - in process]
Source
Davila JA, Henderson L, Kramer JR, Kanwal F, Richardson PA, Duan Z, El-Serag HB.
the Houston Center for Quality of Care and Utilization Studies, The Michael E. DeBakey Veterans Affairs Medical Center, and Baylor College of Medicine, Houston, Texas; University of North Carolina, Chapel Hill, North Carolina; and St. Louis University School of Medicine, St. Louis, Missouri.
Abstract
Background: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with hepatitis C virus (HCV) infection and cirrhosis. However, whether surveillance is being done as recommended is unknown. Objective: To examine the prevalence and determinants of HCC surveillance among HCV-infected patients with cirrhosis in Veterans Affairs (VA) health care facilities in the United States. Design: Retrospective cohort study of HCV-infected patients using data obtained from the national VA Hepatitis C Clinical Case Registry. Setting: 128 VA medical centers. Patients: HCV-infected patients with cirrhosis diagnosed between fiscal years 1998 and 2005. Measurements: Abdominal ultrasonography and measurement of α-fetoprotein for HCC surveillance were identified from administrative data by using a previously validated algorithm. Patients were categorized as having routine (tests done during at least 2 consecutive years in the 4 years after cirrhosis diagnosis), inconsistent (at least 1 test, but not routine), or no surveillance in the 4 years after cirrhosis diagnosis. Predictors of surveillance were identified by using hierarchical random-effects regression. Results: 126 670 patients with HCV were identified; 13 002 (10.1%) had cirrhosis. Approximately 42.0% of patients with cirrhosis received 1 or more HCC surveillance tests within the first year after the cirrhosis index date; however, a decline in receipt of surveillance was observed in the following 2 to 4 years. Among patients with cirrhosis and at least 2 years of follow-up, routine surveillance occurred in 12.0%, inconsistent surveillance in 58.5%, and no surveillance in 29.5%. Lower medical and psychological comorbid conditions, presence of varices, and the absence of decompensated liver disease were associated with a higher likelihood of receiving routine surveillance. Limitations: Hepatocellular carcinoma surveillance tests were indirectly identified from registry data. Physician recommendations could not be captured. Conclusion: Few HCV-infected veterans with cirrhosis received routine HCC surveillance. New strategies are needed to improve the implementation of HCC surveillance in clinical practice. Primary Funding Source: Houston Veterans Affairs Health Services Research and Development Center of Excellence and the National Cancer Institute.
PMID: 21242365 [PubMed - in process]
Source
Boomers may be vulnerable to hepatitis
~ Another article inaccurately stating sex as a
transmission risk of Hepatitis C ~
(see below highlighted in RED)
You may contact the author of the article:
Richard Craver
(336) 727-7376
By RICHARD CRAVERPublished: January 24, 2011
Hepatitis C, like heart disease, is considered as a "silent killer" by health-care officials.
With hepatitis C, the potential victim may have been carrying the virus for decades without knowing it until damage to the liver appears.
About 3.2 million Americans have chronic liver problems related to the virus, and an additional 3 million are not aware they are infected.
Considered particularly vulnerable to the disease are baby boomers — those born between 1946 and 1964 — because of lifestyle decisions made in their younger years.
That's why local physicians focused on infectious diseases are encouraged that two powerful drugs targeting hepatitis C — Vertex Pharmaceuticals' telaprevir and Merck & Co.'s boceprevir — could be available by summer if they gain Food and Drug Administration approval.
Some specialists are drawing comparisons to the early 1990s, when potent combination therapies emerged to treat AIDS.
"These drugs represent a major step forward for treating both new hepatitis C patients and those who have failed therapy," said Dr. Stan Link, an infectious-disease specialist at Forsyth Medical Center.
The new drugs are aimed at blocking an enzyme named protease that's key for the virus to reproduce. But they must be taken together with standard medications that are thought to boost the immune system.
According to the U.S. Centers for Disease Control and Prevention, nearly 70 percent of people with the hepatitis C virus will develop chronic liver disease.
Complications from hepatitis C cause between 4,600 and 12,000 deaths each year in the U.S. Deaths related to the disease are expected to increase to nearly 40,000 a year by 2040.
Transmission risks include injecting illegal drugs — the most common form — getting a tattoo with an unclean needle, having sex with an infected person and receiving donated blood, blood products and organs before 1992.
Hepatitis C "cuts across every segment of society," said Dr. Arun Sanyal of Virginia Commonwealth University in Richmond, the past president of the American Association for the Study of Liver Diseases. "I can tell you our hepatitis C treatment clinic is a great social equalizer."
The current two-drug treatment, which takes 48 weeks, cures about 40 percent of patients with the most common variety of the virus. A cure is defined as no sign of the virus six months after their last dose.
"Those 48 weeks of treatment can be very rough, contributing to depression, hair and weight loss, and severe fatigue," Link said.
Adding one of the new drugs to the regimen is projected to raise the cure rate to 75 percent, while cutting the treatment schedule in half, or to 24 weeks. Telaprevir's main risk is a rash that is sometimes severe, and boceprevir's is anemia.
Link said that while the treatment won't be inexpensive — potentially costing $25,000 to $30,000 a person — he expects most insurance companies will cover it as a less costly alternative to a liver transplant.
The CDC has begun a study at four hospitals to determine whether a one-time hepatitis C test for baby boomers makes sense.
Link and Dr. Marina Nunez, an assistant professor of infectious disease at Wake Forest University Baptist Medical Center, said the potential new drugs could encourage doctors and baby boomers to get tested for hepatitis C.
"We're constantly getting more referrals for hepatitis C treatment, perhaps as more doctors are more conscientious of asking their baby-boomer patients about whether they had any of the risk factors for the virus," Nunez said.
Link said he is recommending that recently diagnosed patients postpone starting therapy until the new drugs are available.
"The potential is there that the odds of their cure rate will be higher," Link said. "Being able to cut the treatment cycle in half will hopefully make it more tolerable for more people."
Source
Also See: New Hope For Hepatitis C, An Often Hidden Disease
Treatment of chronic hepatitis B: Evolution over two decades
J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:138-43. doi: 10.1111/j.1440-1746.2010.06545.x.
Yuen MF, Lai CL.
Department of Medicine, the University of Hong Kong, Queen Mary Hospital, China. mfyuen@hkucc.hku.hk
Abstract
There has been a recent paradigm shift in the indications and endpoints of treatment for chronic hepatitis B (CHB). Hepatitis B e antigen (HBeAg)-negative disease is being increasingly recognized. Antiviral treatment for both HBeAg-positive and HBeAg-negative patients should aim at long-term suppression of HBV DNA, with the ultimate ideal endpoint of hepatitis B surface antigen (HBsAg) seroconversion. Conventional interferon alpha (IFN-α), the only agent licensed in 1991, has been superseded by pegylated IFN-α. HBeAg seroconversion using pegylated IFN-α is 33%, with only 25% of HBeAg-positive patients achieving undetectable HBV DNA by polymerase chain reaction (PCR) assay. Five nucleoside/nucleotide analogues have been licensed since 1998. Lamivudine, an L-nucleoside, is limited by the development of resistance in 76% of patients after 5 years of therapy. Telbivudine, another L-nucleoside, is more potent than lamivudine but resistance still develops in 25% of HBeAg-positive and 11% HBeAg-negative patients after 2 years. Adefovir, an acyclic phosphonate, is relatively weak, but is effective against lamivudine- and telbivudine- resistant mutations, for which it should be used in combination (add-on therapy) rather than substituted. Resistance to adefovir develops slowly, rising to 29% for HBeAg-negative patients by year 5, but more rapidly when used alone for lamivudine-resistant HBV. Currently the two first line nucleoside/nucleotides are entecavir and tenofovir. Entecavir, a cyclopentane (D-nucleoside), is very potent, with 94% of patients having undetectable HBV DNA after 5 years. Resistance develops in only 1.2% of treatment-naïve patients. Tenofovir, another acyclic nucleotide, is more potent with less renal toxicity compared to adefovir. It is effective against lamivudine-resistant mutations when used alone. No resistance to tenofovir has been described after its use for 3 years or longer, often for patients with human immunodeficiency virus/HBV co-infection. With these current, potent antiviral agents associated with very low rates of resistance, long-term HBV DNA suppression and possibly even reversal of cirrhosis can now be achieved in a proportion of patients. In addition, long-term treatment with these antiviral agents is associated with a reduced risk of development of hepatocellular carcinoma.
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
PMID: 21199525 [PubMed - in process]
Source
Yuen MF, Lai CL.
Department of Medicine, the University of Hong Kong, Queen Mary Hospital, China. mfyuen@hkucc.hku.hk
Abstract
There has been a recent paradigm shift in the indications and endpoints of treatment for chronic hepatitis B (CHB). Hepatitis B e antigen (HBeAg)-negative disease is being increasingly recognized. Antiviral treatment for both HBeAg-positive and HBeAg-negative patients should aim at long-term suppression of HBV DNA, with the ultimate ideal endpoint of hepatitis B surface antigen (HBsAg) seroconversion. Conventional interferon alpha (IFN-α), the only agent licensed in 1991, has been superseded by pegylated IFN-α. HBeAg seroconversion using pegylated IFN-α is 33%, with only 25% of HBeAg-positive patients achieving undetectable HBV DNA by polymerase chain reaction (PCR) assay. Five nucleoside/nucleotide analogues have been licensed since 1998. Lamivudine, an L-nucleoside, is limited by the development of resistance in 76% of patients after 5 years of therapy. Telbivudine, another L-nucleoside, is more potent than lamivudine but resistance still develops in 25% of HBeAg-positive and 11% HBeAg-negative patients after 2 years. Adefovir, an acyclic phosphonate, is relatively weak, but is effective against lamivudine- and telbivudine- resistant mutations, for which it should be used in combination (add-on therapy) rather than substituted. Resistance to adefovir develops slowly, rising to 29% for HBeAg-negative patients by year 5, but more rapidly when used alone for lamivudine-resistant HBV. Currently the two first line nucleoside/nucleotides are entecavir and tenofovir. Entecavir, a cyclopentane (D-nucleoside), is very potent, with 94% of patients having undetectable HBV DNA after 5 years. Resistance develops in only 1.2% of treatment-naïve patients. Tenofovir, another acyclic nucleotide, is more potent with less renal toxicity compared to adefovir. It is effective against lamivudine-resistant mutations when used alone. No resistance to tenofovir has been described after its use for 3 years or longer, often for patients with human immunodeficiency virus/HBV co-infection. With these current, potent antiviral agents associated with very low rates of resistance, long-term HBV DNA suppression and possibly even reversal of cirrhosis can now be achieved in a proportion of patients. In addition, long-term treatment with these antiviral agents is associated with a reduced risk of development of hepatocellular carcinoma.
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
PMID: 21199525 [PubMed - in process]
Source
Hepatic steatosis and hepatitis C: Still unhappy bedfellows?
J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:96-101. doi: 10.1111/j.1440-1746.2010.06542.x.
Hwang SJ, Lee SD.
Department of Family Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Abstract
Hepatic steatosis is commonly seen in patients with chronic hepatitis C virus (HCV) infection, and the prevalence is much higher prevalence than in the general population or in patients with chronic hepatitis B. Hepatic steatosis in patients with chronic hepatitis C can be due to alcohol consumption and host metabolic factors such as high body mass index (BMI), obesity, hyperlipidemia, metabolic syndrome and diabetes mellitus in which insulin resistance plays an important role. However, in genotype 3 HCV infection, hepatic steatosis can result from direct viral cytopathic effect. Demographic and clinical characteristics associated with hepatic steatosis in patients with chronic hepatitis C including older age, higher BMI, more genotype 3 infection, and higher mean serum levels of triglyceride, alanine aminotransferase and γ-glutamyl transpeptidase. The clinical relevance of hepatic steatosis in patients with chronic hepatitis C includes a close correlation with hepatic fibrosis, and a poor response to combination peginterferon and ribavirin treatment. In addition, hepatic steatosis has been reported to associate with increased frequency of hepatocellular carcinoma in patients with chronic HCV infection. Whether life style modification such as weight reduction or adding an insulin resistance reducing agent such as metformin or thiazolidinediones combined with current standard peginterferon plus ribavirin treatment will benefit to the chronic hepatitis C patients with hepatic steatosis deserves further evaluation.
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
PMID: 21199519 [PubMed - in process]
Source
Hwang SJ, Lee SD.
Department of Family Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Abstract
Hepatic steatosis is commonly seen in patients with chronic hepatitis C virus (HCV) infection, and the prevalence is much higher prevalence than in the general population or in patients with chronic hepatitis B. Hepatic steatosis in patients with chronic hepatitis C can be due to alcohol consumption and host metabolic factors such as high body mass index (BMI), obesity, hyperlipidemia, metabolic syndrome and diabetes mellitus in which insulin resistance plays an important role. However, in genotype 3 HCV infection, hepatic steatosis can result from direct viral cytopathic effect. Demographic and clinical characteristics associated with hepatic steatosis in patients with chronic hepatitis C including older age, higher BMI, more genotype 3 infection, and higher mean serum levels of triglyceride, alanine aminotransferase and γ-glutamyl transpeptidase. The clinical relevance of hepatic steatosis in patients with chronic hepatitis C includes a close correlation with hepatic fibrosis, and a poor response to combination peginterferon and ribavirin treatment. In addition, hepatic steatosis has been reported to associate with increased frequency of hepatocellular carcinoma in patients with chronic HCV infection. Whether life style modification such as weight reduction or adding an insulin resistance reducing agent such as metformin or thiazolidinediones combined with current standard peginterferon plus ribavirin treatment will benefit to the chronic hepatitis C patients with hepatic steatosis deserves further evaluation.
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
PMID: 21199519 [PubMed - in process]
Source
Fatty liver disease associated with cardiovascular risk in patients with HIV
Michael Carter
Published: 24 January 2011
Hardening of the arteries is common in HIV-positive patients, and is associated with fatty liver disease, US investigators report in the online edition of HIV Medicine.
“HIV-infected persons with fatty liver disease may warrant early cardiovascular assessment and institution of risk reduction methods,” comment the researchers.
Cardiovascular disease is an increasingly important cause of illness and death in patients with HIV. Studies conducted in HIV-negative individuals have shown that the presence of a fatty liver is associated with hardening of the coronary artery (atherosclerosis), an important risk factor for heart disease.
A team of investigators lead by Dr Nancy Crum-Cianflone wished to see if this was also the case for HIV-infected individuals.
They write: “Given that liver test abnormalities and fatty liver disease are common in among HIV infected persons, determining their relationship with coronary artery atherosclerosis may be helpful in the development of screening guidelines and risk stratification for underlying cardiovascular risk in this population.”
Between 2008 and 2010 they undertook a cross sectional study involving 223 HIV-positive adults. All the patients had a CT scan which checked for hardening, or calcification, of the coronary artery and fatty liver disease.
Atherosclerosis in the coronary artery was diagnosed if any calcification was detected (a score above 0), and a score above 100 was considered clinicially significant. Fatty liver was defined as a liver-to-spleen ratio < 0.1.
Information was also gathered on the patients’ demographics, CD4 cell count and viral load, use of antiretroviral drugs, lipid levels, and medical histories. A series of statistical analyses were then performed to see which factors were associated with hardening of the coronary artery.
With a median age of 43 years (range 36-50), the patients were relatively young. Risk factors for cardiovascular disease were common, and 39% had hypertension and 6% diabetes. Fatty liver can be a complication of viral hepatitis, but only 3% of the study population were co-infected with hepatitis C.
Most patients (83%) were taking antiretroviral therapy, 70% had an undetectable viral load and median CD4 cell count was 586 cells/mm3.
CT scanning showed that 34% of individuals had some hardening of the coronary artery, and that this was clinically significant for 8% of patients. Fatty liver was diagnosed in 13% of individuals.
Prevalence of fatty liver for patients with no evidence of hardening of the coronary artery was 8%. But this increased to 18% for individuals with a calcification score between 1-100, and was 41% for patients with clinically significant arterial hardening.
Overall, 59% of patients with fatty liver also had coronary atherosclerosis, and the correlation between the two conditions was significant (p = 0.02).
Statistical analysis that controlled for potentially confounding factors showed that three factors were significantly associated with calcification of the coronary artery: older age (each ten year increase, p < 0.01); fatty liver disease (p < 0.01), and hypertension (p < 0.01).
The relationship between hardening of the coronary artery and fatty liver disease was extremely robust, and was unaltered when the investigators excluded the small number of patients with hepatitis C, or those with metabolic syndrome. It was also present when patients with alcohol use were excluded from analysis.
“In our study, HIV-infected persons, despite their relatively young age, had a high prevalence of subclinical heart disease,” write the authors. They believe rheir results “emphasize the importance of cardiovascular disease among HIV-infected patients and suggest that addressing underlying heart disease may be an important component of further normalizing the life expectancy of this group.”
Inflammation could, the authors believe, be causing both the hardening of the arteries and the fatty liver disease observed in their patients.
Dr Crum-Cianflone and her colleagues conclude: “Fatty liver disease is associated with underlying cardiovascular disease and should be considered as a novel marker for risk stratification among HIV-infected persons.”
Reference
Crum-Cianflone N et al. Fatty liver disease is associated with underlying cardiovascular disease in HIV-infected persons. HIV Med, online edition (DOI: 10.1111/j.1468-1293.2010.00904.x), 2011 (click here for the free abstract).
Source
Published: 24 January 2011
Hardening of the arteries is common in HIV-positive patients, and is associated with fatty liver disease, US investigators report in the online edition of HIV Medicine.
“HIV-infected persons with fatty liver disease may warrant early cardiovascular assessment and institution of risk reduction methods,” comment the researchers.
Cardiovascular disease is an increasingly important cause of illness and death in patients with HIV. Studies conducted in HIV-negative individuals have shown that the presence of a fatty liver is associated with hardening of the coronary artery (atherosclerosis), an important risk factor for heart disease.
A team of investigators lead by Dr Nancy Crum-Cianflone wished to see if this was also the case for HIV-infected individuals.
They write: “Given that liver test abnormalities and fatty liver disease are common in among HIV infected persons, determining their relationship with coronary artery atherosclerosis may be helpful in the development of screening guidelines and risk stratification for underlying cardiovascular risk in this population.”
Between 2008 and 2010 they undertook a cross sectional study involving 223 HIV-positive adults. All the patients had a CT scan which checked for hardening, or calcification, of the coronary artery and fatty liver disease.
Atherosclerosis in the coronary artery was diagnosed if any calcification was detected (a score above 0), and a score above 100 was considered clinicially significant. Fatty liver was defined as a liver-to-spleen ratio < 0.1.
Information was also gathered on the patients’ demographics, CD4 cell count and viral load, use of antiretroviral drugs, lipid levels, and medical histories. A series of statistical analyses were then performed to see which factors were associated with hardening of the coronary artery.
With a median age of 43 years (range 36-50), the patients were relatively young. Risk factors for cardiovascular disease were common, and 39% had hypertension and 6% diabetes. Fatty liver can be a complication of viral hepatitis, but only 3% of the study population were co-infected with hepatitis C.
Most patients (83%) were taking antiretroviral therapy, 70% had an undetectable viral load and median CD4 cell count was 586 cells/mm3.
CT scanning showed that 34% of individuals had some hardening of the coronary artery, and that this was clinically significant for 8% of patients. Fatty liver was diagnosed in 13% of individuals.
Prevalence of fatty liver for patients with no evidence of hardening of the coronary artery was 8%. But this increased to 18% for individuals with a calcification score between 1-100, and was 41% for patients with clinically significant arterial hardening.
Overall, 59% of patients with fatty liver also had coronary atherosclerosis, and the correlation between the two conditions was significant (p = 0.02).
Statistical analysis that controlled for potentially confounding factors showed that three factors were significantly associated with calcification of the coronary artery: older age (each ten year increase, p < 0.01); fatty liver disease (p < 0.01), and hypertension (p < 0.01).
The relationship between hardening of the coronary artery and fatty liver disease was extremely robust, and was unaltered when the investigators excluded the small number of patients with hepatitis C, or those with metabolic syndrome. It was also present when patients with alcohol use were excluded from analysis.
“In our study, HIV-infected persons, despite their relatively young age, had a high prevalence of subclinical heart disease,” write the authors. They believe rheir results “emphasize the importance of cardiovascular disease among HIV-infected patients and suggest that addressing underlying heart disease may be an important component of further normalizing the life expectancy of this group.”
Inflammation could, the authors believe, be causing both the hardening of the arteries and the fatty liver disease observed in their patients.
Dr Crum-Cianflone and her colleagues conclude: “Fatty liver disease is associated with underlying cardiovascular disease and should be considered as a novel marker for risk stratification among HIV-infected persons.”
Reference
Crum-Cianflone N et al. Fatty liver disease is associated with underlying cardiovascular disease in HIV-infected persons. HIV Med, online edition (DOI: 10.1111/j.1468-1293.2010.00904.x), 2011 (click here for the free abstract).
Source
Merck Says Hepatitis B Vaccine Safe; Unrelated to TG Swab Recall
By Nazvi Careem
Published Jan 24, 2011
Healthcare company Merck said its hepatitis B and hepatitis C medicines are safe to use despite the recent recall of Triad Group alcohol prep pads by FDA.
New Jersey: The hepatitis B vaccine and hepatitis C powder produced by healthcare company Merck are safe and are not affected by the recall of potentially contaminated Triad Group alcohol swab products, according to the manufacturer.
In a press release issued on January 23, Merck moved to reassure consumers its medicines, which may be co-packaged with Triad Group products, were not affected by the recent recall initiated by the FDA and the Triad Group.
It said consumers should continue to use its Intron A and Pegintron medicines but discard the alcohol prep pads that are included in the packages.
“It is important to note that the Merck medicines are not contaminated, and should continue to be used in accordance with the package insert, and as directed by a healthcare provider, except the alcohol prep pad should be discarded,” said the press release (http://www.merck.com/newsroom/news-release-archive/prescription-medicine-news/2011_0123.html).
On January 3, the FDA and Triad Group, a manufacturer of over-the-counter products, announced the recall of alcohol prep pads, swabs and swabsticks over concerns about possible contamination with Bacillus cereus.
Disinfectant
The recall affected products marked as “STERILE” in addition to non-sterile items with the FDA warning that their use may lead to life-threatening infections, particularly among high-risk groups such as immune-suppressed and surgical patients.
The pads and swabs are usually used as a disinfectant by wiping an area of the body before an injection.
The FDA stressed that the recall is confined to Triad Group products and not the items from other manufacturers that it might be packaged with (http://www.fda.gov/Safety/MedWatch/default.htm, last checked January 24, 2011).
The Merck products accompanying the potentially contaminated Triad Group swabs are sold in Latin America, excluding Brazil, Canada, Europe and Asia Pacific, excluding Japan.
The company said its medicines distributed in the United States are not affected by the recall of Triad Group products.
Hepatitis B vaccine
Intron A contains the man-made protein Interferon and is used in the treatment of chronic hepatitis B, in addition to hairy cell leukaemia, malignant melanoma, follicular lymphoma, AIDS-related Kaposi’s sarcoma, chronic hepatitis C and condylomata acuminata.
Pegintron is a powder that is used to make a solution used in the treatment of chronic hepatitis C in patients three years and older.
Merck said, after talks with health experts at regional government level, it would start to package orders for countries minus the alcohol prep pads until another source of the material can be identified.
It will also urge consumers in affected markets to discontinue using the pads, swabs and swabsticks because of the risk of contamination.
In addition, Merck plans education programmes in the various countries so patients can be fully informed on the products and its risks.
The information will be made available to regulatory agencies in respective countries and those conducting clinical trials using the products.
Source
Published Jan 24, 2011
Healthcare company Merck said its hepatitis B and hepatitis C medicines are safe to use despite the recent recall of Triad Group alcohol prep pads by FDA.
New Jersey: The hepatitis B vaccine and hepatitis C powder produced by healthcare company Merck are safe and are not affected by the recall of potentially contaminated Triad Group alcohol swab products, according to the manufacturer.
In a press release issued on January 23, Merck moved to reassure consumers its medicines, which may be co-packaged with Triad Group products, were not affected by the recent recall initiated by the FDA and the Triad Group.
It said consumers should continue to use its Intron A and Pegintron medicines but discard the alcohol prep pads that are included in the packages.
“It is important to note that the Merck medicines are not contaminated, and should continue to be used in accordance with the package insert, and as directed by a healthcare provider, except the alcohol prep pad should be discarded,” said the press release (http://www.merck.com/newsroom/news-release-archive/prescription-medicine-news/2011_0123.html).
On January 3, the FDA and Triad Group, a manufacturer of over-the-counter products, announced the recall of alcohol prep pads, swabs and swabsticks over concerns about possible contamination with Bacillus cereus.
Disinfectant
The recall affected products marked as “STERILE” in addition to non-sterile items with the FDA warning that their use may lead to life-threatening infections, particularly among high-risk groups such as immune-suppressed and surgical patients.
The pads and swabs are usually used as a disinfectant by wiping an area of the body before an injection.
The FDA stressed that the recall is confined to Triad Group products and not the items from other manufacturers that it might be packaged with (http://www.fda.gov/Safety/MedWatch/default.htm, last checked January 24, 2011).
The Merck products accompanying the potentially contaminated Triad Group swabs are sold in Latin America, excluding Brazil, Canada, Europe and Asia Pacific, excluding Japan.
The company said its medicines distributed in the United States are not affected by the recall of Triad Group products.
Hepatitis B vaccine
Intron A contains the man-made protein Interferon and is used in the treatment of chronic hepatitis B, in addition to hairy cell leukaemia, malignant melanoma, follicular lymphoma, AIDS-related Kaposi’s sarcoma, chronic hepatitis C and condylomata acuminata.
Pegintron is a powder that is used to make a solution used in the treatment of chronic hepatitis C in patients three years and older.
Merck said, after talks with health experts at regional government level, it would start to package orders for countries minus the alcohol prep pads until another source of the material can be identified.
It will also urge consumers in affected markets to discontinue using the pads, swabs and swabsticks because of the risk of contamination.
In addition, Merck plans education programmes in the various countries so patients can be fully informed on the products and its risks.
The information will be made available to regulatory agencies in respective countries and those conducting clinical trials using the products.
Source
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